Method for treating HIV with Cabotegravir and Rilpivirine

ABSTRACT

Invented are methods for treating HIV in a human in need thereof which comprises the administration of a therapeutically effective amount of a combination of cabotegravir or a pharmaceutically acceptable salt thereof and rilpivirine or a pharmaceutically acceptable salt thereof, to such human.

FIELD OF THE INVENTION

This invention relates to a method of treating HIV in a human by the invivo administration of cabotegravir or a pharmaceutically acceptablesalt thereof, in combination with rilpivirine or a pharmaceuticallyacceptable salt thereof.

BACKGROUND OF THE INVENTION

The contemporary standard of care for first-line treatment of HIV-1infection in adults naive to antiretroviral therapy (ART) is a regimenof ≥3 antiretroviral agents that includes two nucleoside reversetranscriptase inhibitors (NRTIs) and one other drug from either theboosted protease inhibitor (PI), integrase strand transfer inhibitor(INSTI), or non-nucleoside reverse transcriptase inhibitor (NNRTI)classes. However, concerns exist regarding the need for lifelong therapywith drugs that have diverse safety and tolerability profiles. Thus,2-drug regimens (2DRs) capable of inducing and/or maintaining virologicsuppression while decreasing lifetime cumulative drug exposure andpotential long-term toxicities would represent an alternative treatmentoption for people living with HIV-1 infection.

Trials evaluating early (2000-2014) 2DRs yielded inconclusive results,perhaps partially because of small sample sizes, short treatmentdurations, and limitations of available treatments. The AIDS ClinicalTrials Group Study A5142 team found that the virologic efficacy of a 2DRcomprising efavirenz plus ritonavir-boosted lopinavir (n=250) wassimilar to that of efavirenz plus 2 NRTIs (n=250) through 96 weeks oftreatment in ART-naive participants. However, this 2DR was associatedwith increased incidence of drug resistance. Likewise, the PROGRESSstudy demonstrated that a 2DR of ritonavir-boosted lopinavir plusraltegravir (n=101) exerts a similar antiviral effect in ART-naiveparticipants through Week 96 compared with the 3-drug regimen (3DR) ofritonavir-boosted lopinavir plus tenofovir disoproxilfumarate/emtricitabine (n=105), but this study mostly enrolledparticipants with viral loads <100,000 copies/mL and CD4+ cell counts≥200 cells/mm. The GARDEL study demonstrated the non-inferior virologicefficacy of open-label ritonavir-boosted lopinavir plus lamivudine(n=214) compared with ritonavir-boosted lopinavir plus 2 NRTIs (n=202)in ART-naive participants after 48 weeks of treatment. However, these2DRs include ritonavir-boosted PIs, which are associated with a varietyof metabolic syndromes and cardiovascular-related disease and may negateany anticipated benefit in terms of decreased drug exposure andcumulative toxicity. These studies illustrate both the potential of 2DRsas an option for ART and the importance of selecting drugs withappropriate and complementary virologic and clinical properties.

Cabotegravir (GSK1265744) is an analogue of the integrase strandtransfer inhibitor (INSTI) dolutegravir that exhibits subnanomolarpotency and antiviral activity against a broad range of HIV-1 strains.Oral administration of cabotegravir once daily has exhibited acceptablesafety and tolerability profiles, a long half-life (40 h), and fewdrug-drug interactions. Rilpivirine (TMC278) is a non-nucleoside reversetranscriptase inhibitor (NNRTI) that is approved as a 25 mg once-dailyoral medication for HIV-1 treatment.

In the LATTE-2 trial, patients were first put on a regimen of oralcabotegravir and abacavir/lamivudine for 20 weeks. After the inductionperiod, suppressed patients were randomized 2:2:1 to receive either thelong-acting injectable cabotegravir and rilpivirine every 4 or every 8weeks, or to continue the 3-drug oral regimen. Patients on thelong-acting regimen were extended through to 160 weeks and patients onthe oral regimen were given the option of transitioning to the regimenevery 4 or every 8 weeks at week 96. At 160 weeks, 104 of 115participants (90%) and 95 of 115 participants (83%) receiving theinjectable regimen, every 8 and 4 weeks respectively, remained virallysuppressed.

SUMMARY OF THE INVENTION

This invention comprises a method of treating HIV in a human in needthereof which comprises the administration of a therapeuticallyeffective amount of a combination of: cabotegravir or a pharmaceuticallyacceptable salt thereof, and rilpivirine or a pharmaceuticallyacceptable salt thereof. Alternatively, an aspect of the embodimentincludes use of cabotegravir or a salt thereof and rilpivirine or a saltthereof in the manufacture of a medicament for use in the treatment ofHIV infection. Alternatively, an aspect of the embodiment includescabotegravir or a salt thereof and rilpivirine or a salt thereof for usein the treatment of HIV infection.

According to first main embodiment, a combination, in particular a2-drug co-packaged product of cabotegravir, a human immunodeficiencyvirus type-1 (HIV-1) integrase strand transfer inhibitor (INSTI), andrilpivirine, an HIV-1 non-nucleoside reverse transcriptase inhibitor(NNRTI), (collectively “the Combination”) is indicated as a completeregimen for the treatment of HIV-1 infection in adults to replace thecurrent antiretroviral regimen in those who are virologically suppressed(HIV-1 RNA less than 50 copies per mL) and who have no known orsuspected resistance to either cabotegravir or rilpivirine. According toan embodiment, there is provided cabotegravir or a salt thereof andrilpivirine or a salt thereof for use in the treatment of HIV infectionin adults as a complete regimen to replace the current antiretroviralregimen in those who are virologically suppressed (HIV-1 RNA less than50 copies per mL) and who have no known or suspected resistance toeither cabotegravir or rilpivirine. According to an embodiment, there isprovided cabotegravir or a salt thereof and rilpivirine or a saltthereof for use in the treatment of HIV infection in adults as acomplete regimen to replace the current antiretroviral regimen in thosewho are virologically suppressed (HIV-1 RNA less than 50 copies per mL)and who have no known or suspected resistance to either cabotegravir orrilpivirine and who have no prior virological failure with agents of theNNRTI and INSTI class. According to an embodiment, there is providedcabotegravir or a salt thereof for use in the treatment of HIV infectionin adults as a complete regimen to replace the current antiretroviralregimen in those who are virologically suppressed (HIV-1 RNA less than50 copies per mL) and who have no known or suspected resistance toeither cabotegravir or rilpivirine, wherein cabotegravir or a saltthereof is used in combination with rilpivirine or a salt thereof.According to an embodiment, there is provided cabotegravir or a saltthereof for use in the treatment of HIV infection in adults as acomplete regimen to replace the current antiretroviral regimen in thosewho are virologically suppressed (HIV-1 RNA less than 50 copies per mL)and who have no known or suspected resistance to either cabotegravir orrilpivirine and who have no prior virological failure with agents of theNNRTI and INSTI class, wherein cabotegravir or a salt thereof is used incombination with rilpivirine or a salt thereof. According to anembodiment, there is provided rilpivirine or a salt thereof for use inthe treatment of HIV infection in adults as a complete regimen toreplace the current antiretroviral regimen in those who arevirologically suppressed (HIV-1 RNA less than 50 copies per mL) and whohave no known or suspected resistance to either cabotegravir orrilpivirine, wherein rilpivirine or a salt thereof is used incombination with cabotegravir or a salt thereof. According to anembodiment, there is provided rilpivirine or a salt thereof for use inthe treatment of HIV infection in adults as a complete regimen toreplace the current antiretroviral regimen in those who arevirologically suppressed (HIV-1 RNA less than 50 copies per mL) and whohave no known or suspected resistance to either cabotegravir orrilpivirine and who have no prior virological failure with agents of theNNRTI and INSTI class, wherein rilpivirine or a salt thereof is used incombination with cabotegravir or a salt thereof.

According to a second main embodiment, a method of treating HIV-1 isprovided, comprising regularly administering intramuscular injections ofcabotegravir or a salt thereof and rilpivirine or a salt thereof,subsequent to at least one said intramuscular injection of each ofcabotegravir or a salt thereof and rilpivirine or a salt thereof,discontinuing one or both of said regularly administered intramuscularinjections, and replacing the one or more discontinued intramuscularinjection with regularly administered oral therapy. Alternatively,according to an aspect of this embodiment, there is providedcabotegravir or a salt thereof and rilpivirine or a salt thereof for usein therapy, in particular in the treatment of HIV infection, whereinsaid therapy, in particular the treatment of HIV infection, comprisesregularly administering intramuscular injections of said cabotegravir ora salt thereof and rilpivirine or a salt thereof, subsequent to at leastone said intramuscular injection of each of cabotegravir or a saltthereof and rilpivirine or a salt thereof, discontinuing one or both ofsaid regularly administered intramuscular injections, and replacing theone or more discontinued intramuscular injection with regularlyadministered oral therapy.

According to a third main embodiment, a method of treating HIV isprovided, comprising regularly administering intramuscular injections ofcabotegravir or a salt thereof and rilpivirine or a salt thereof,subsequent to at least one said intramuscular injection of each ofcabotegravir or a salt thereof and rilpivirine or a salt thereof,discontinuing one or both of said regularly administered intramuscularinjections, and reestablishing intramuscular administration of the oneor both cabotegravir or a salt thereof and rilpivirine or a salt thereofby first administering a loading dose of the discontinued cabotegraviror a salt thereof and/or rilpivirine or a salt thereof, and thencontinuing the regular administration of the intramuscular injections.Alternatively, according to an aspect of this embodiment, there isprovided cabotegravir or a salt thereof and rilpivirine or a saltthereof for use in therapy, in particular in the treatment of HIVinfection, wherein the therapy, in particular the treatment of HIVinfection, comprises regularly administering intramuscular injectionsthereof subsequent to at least one said intramuscular injection of eachof cabotegravir or a salt thereof and rilpivirine or a salt thereof,discontinuing one or both of said regularly administered intramuscularinjections, and reestablishing intramuscular administration of the oneor both cabotegravir or a salt thereof and rilpivirine or a saltthereof, by first administering a loading dose of the discontinuedcabotegravir or a salt thereof and/or rilpivirine or a salt thereof, andthen continuing the regular administration of the intramuscularinjections.

DETAILED DESCRIPTION OF THE INVENTION First Main Embodiment

According to first main embodiment, a combination, in particular a2-drug co-packaged product of cabotegravir, a human immunodeficiencyvirus type-1 (HIV-1) integrase strand transfer inhibitor (INSTI), andrilpivirine, an HIV-1 non-nucleoside reverse transcriptase inhibitor(NNRTI), (collectively “the Combination”) is indicated as a completeregimen for the treatment of HIV-1 infection in adults to replace thecurrent antiretroviral regimen in those who are virologically suppressed(HIV-1 RNA less than 50 copies per mL) and who have no known orsuspected resistance to either cabotegravir or rilpivirine. In oneembodiment, the Combination consists of a cabotegravir long-actingformulation and a rilpivirine long acting formulation. In oneembodiment, the Combination consists of a cabotegravir long-actingintramuscular injection and a rilpivirine long acting intramuscularinjection.

The Combination is indicated as a complete regimen for the treatment ofhuman immunodeficiency virus type 1 (HIV-1) infection in adults toreplace the current antiretroviral regimen in those who arevirologically suppressed (HIV-1 RNA less than 50 copies per mL) and whohave no known or suspected resistance to either cabotegravir orrilpivirine. In an embodiment, the Combination is indicated as acomplete regimen for the treatment of human immunodeficiency virus type1 (HIV-1) infection in adults to replace the current antiretroviralregimen in those who are virologically suppressed (HIV-1 RNA less than50 copies per mL) and who have no known or suspected resistance toeither cabotegravir or rilpivirine and who have no prior virologicalfailure with agents of the NNRTI and INSTI class.

According to an aspect of the main embodiment, oral lead-in dosing toassess tolerability of the combination, where an oral lead-in (one 30-mgtablet of cabotegravir and one 25-mg tablet of rilpivirine once daily,for instance one tablet comprising 31.62 mg cabotegravir sodium and onetablet comprising 27.5 mg rilpivirine hydrochloride) is to be used forapproximately 1 month (at least 28 days) prior to the initiation of theCombination to assess the tolerability of cabotegravir and rilpivirine.

According to another aspect of the main embodiment, the Combination isadministered by intramuscular injections. Specifically,

Initiation Injections (3-mL Dosing Kit)

Initiate injections on the final day of oral lead-in. The recommendedinitial injection doses of the Combination in adults are a single 3-mL(600 mg) intramuscular injection of cabotegravir and a single 3-mL (900mg) intramuscular injection of rilpivirine. Cabotegravir and rilpivirineshould be administered at separate gluteal injection sites during thesame visit.

Continuation Injections (2-mL Dosing Kit)

After the initiation injections, the recommended continuation injectiondoses of the Combination in adults are a single 2-mL (400 mg)intramuscular injection of cabotegravir and a single 2-mL (600 mg)intramuscular injection of rilpivirine monthly. Cabotegravir andrilpivirine should be administered at separate gluteal injection sitesduring the same visit. Patients may be given the Combination up to 7days before or after the date of the monthly 2-mL injection dosingschedule.

TABLE 1 Recommended Dosing Schedule in Adults Intramuscular OralInitiation Injections Intramuscular Lead-In (One-Time Dosing)Continuation (at Least At Month 2 Injections 28 Days) (On the Last Dayof (Once Monthly) Drug Month 1 Oral Lead-In Dosing) Month 3 OnwardsCabotegravir 30 mg 3 mL (600 mg) 2 mL (400 mg) once daily Rilpivirine 25mg 3 mL (900 mg) 2 mL (600 mg) once daily

According to another aspect of the main embodiment, adherence to themonthly injection dosing schedule is strongly recommended. Patients whomiss a scheduled injection visit should be clinically reassessed toensure resumption of therapy remains appropriate. Refer to Table 2 fordosing recommendations after missed injections.

TABLE 2 Injection Dosing Recommendations after Missed Injections or OralTherapy Time Since Last Injection Recommendation <2 months Continue withthe monthly 2-mL injection dosing schedule as soon as possible. ≥2months Re-initiate the patient on the 3-mL dose, and then continue tofollow the monthly 2-mL injection dosing schedule.

According to another aspect of the main embodiment, injections must beadministered by a healthcare professional. A complete dose requires 2injections: one injection of cabotegravir and one injection ofrilpivirine. Injections of the Combination are intended forintramuscular use only. Consider the body mass index (BMI) of thepatient to ensure that the needle length is sufficient to reach thegluteus muscle. Administer each injection at separate gluteal injectionsites during the same visit. The ventrogluteal site is recommended.

According to another aspect of the main embodiment, cabotegravir andrilpivirine are suspensions for intramuscular injection that do not needfurther dilution or reconstitution. The administration order ofcabotegravir and rilpivirine injections is not important. Beforepreparing the injections, remove the Combination from the refrigeratorand wait at least 15 minutes to allow the medications to come to roomtemperature. Shake each vial of the Combination vigorously so that thesuspensions look uniform before injecting. Small air bubbles areexpected and acceptable. Parenteral drug products should be inspectedvisually for particulate matter and discoloration prior toadministration whenever solution and container permit. The cabotegravirvial has a brown tint to the glass which may limit visual inspection.Discard the Combination if either medicine exhibits particulate matteror discoloration.

According to an aspect, oral lead-in is provided by cabotegravir sodium,in particular 30 mg base equivalent. According to an aspect, orallead-in is provided by rilpivirine hydrochloride, in particular 25 mgbase equivalent. According to an aspect, cabotegravir injection, inparticular intramuscular injection, is provided by cabotegravir base. Inan aspect, rilpivirine injection, in particular intramuscular injection,is provided by rilpivirine base.

According to another aspect of the main embodiment, the Combinationcontains cabotegravir 200 mg/mL as a white to light pink, free-flowingextended-release injectable suspension and rilpivirine 300 mg/mL as awhite to off-white extended-release injectable suspension, co-packagedas follows:

2-mL Dosing Kit

-   -   single-dose vial of 400 mg of cabotegravir    -   single-dose vial of 600 mg of rilpivirine

3-mL Dosing Kit

-   -   single-dose vial of 600 mg of cabotegravir    -   single-dose vial of 900 mg of rilpivirine

In an embodiment, the above-mentioned vials of cabotegravir andrilpivirine are not co-packed, but are packed separately.

According to another aspect of the main embodiment, the Combination iscontraindicated in patients:

-   -   with previous hypersensitivity reaction to cabotegravir or        rilpivirine. receiving the following coadministered drugs for        which significant decreases in cabotegravir and/or rilpivirine        plasma concentrations may occur due to uridine diphosphate        (UDP)-glucuronosyl transferase (UGT)1A1 and/or cytochrome P450        (CYP)3A enzyme induction, which may result in loss of virologic        response:        -   Anticonvulsants: Carbamazepine, oxcarbazepine,            phenobarbital, phenytoin        -   Antimycobacterials: Rifabutin, rifampin, rifapentine        -   Glucocorticoid (systemic): Dexamethasone (more than a            single-dose treatment)        -   Herbal product: St John's wort (Hypericum perforatum)

According to another aspect of the main embodiment, precautions aretaken prior to and during treatment with the Combination. Severe skinand hypersensitivity reactions have been reported during postmarketingexperience with oral rilpivirine-containing regimens including cases ofDrug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Whilesome skin reactions were accompanied by constitutional symptoms such asfever, other skin reactions were associated with organ dysfunctions,including elevations in hepatic serum biochemistries. During the Phase 3clinical trials of oral rilpivirine, treatment-related rashes with atleast Grade 2 severity were reported in 3% of subjects; however, noGrade 4 rash was reported.

According to another aspect of the main embodiment, the Combination isadministered by intramuscular injections alone. Specifically, theintramuscular injections are administered without following oral leadin. In an embodiment, progressing to intramuscular injections withoutoral lead in demonstrate similar efficacy to treatment including orallead in prior to intramuscular injections. ART-naive participantsachieving virologic suppression (HIV-1 RNA <50 c/mL) with daily oraldolutegravir/abacavir/lamivudine during the 20-week Induction Phase byrandomizing and administering (1:1) either continue daily oraldolutegravir/abacavir/lamivudine or switch to LA. Participantsrandomizing with monthly Combination therapy received an oral lead in ofthe Combination once daily for ≥4 weeks before receiving monthlyinjectable Combination. After completing the Maintenance Phase at Week(W) 100, dolutegravir/abacavir/lamivudine arm participants switched toCombination therapy (Extension Switch population) either directly(Direct to Inject [DTI] arm) or with a 4-week oral lead in. Endpointsassessed at W124 for the Extension Switch population included viral load(HIV-1 RNA ≥50 c/mL and <50 c/mL), confirmed virologic failure (CVF; twoconsecutive HIV-1 RNA ≥200 c/mL), safety and tolerability aspects.Switching to Combination therapy without oral lead in demonstratedsimilar efficacy to treatment including oral lead in at W124. Safety andtolerability were comparable between treatment groups. This suggests theCombination, with optional oral lead in, is a well-tolerated andeffective maintenance therapy for virologically suppressed patientsliving with HIV-1.

According to another aspect of the main embodiment, the Combination isused to treat Hepatitis C. In one embodiment, the Combination is used totreat Hepatitis C HIV co-infection. Open-label, international phase 3studies that evaluated switching to monthly intramuscular injections ofthe Combination formulations of CAB (CAB LA)+RPV (RPV LA) vs continuingoral standard of care ART in adult participants with HIV-1 RNA <50 c/mL.In the Combination arm, participants initially received oral CAB 30mg+RPV 25 mg once daily for 4 weeks, to assess safety and tolerability,before starting monthly injectable therapy. Participants with chronicHCV infection without cirrhosis who do not require HCV treatment wereanalyzed for proportion with plasma HIV-1 RNA >50 c/mL and <50 c/mL(Snapshot algorithm), change from baseline in CD4+ cell count, generaland hepatic safety, and PK parameters. The combination demonstratedsimilar efficacy and safety to oral standard of care therapy inparticipants co-infected with HIV and HCV.

Hypersensitivity reactions have been reported in association with otherintegrase inhibitors. These reactions were characterized by rash,constitutional findings, and sometimes organ dysfunction, includingliver injury. While no such reactions have been observed in Phase 2 and3 clinical trials in association with cabotegravir, remain vigilant anddiscontinue the Combination if a hypersensitivity reaction is suspected.

Discontinue the Combination immediately if signs or symptoms of severeskin or hypersensitivity reactions develop (including, but not limitedto, severe rash, or rash accompanied by fever, general malaise, fatigue,muscle or joint aches, blisters, mucosal involvement [oral blisters orlesions], conjunctivitis, facial edema, hepatitis, eosinophilia,angioedema). Clinical status, including liver transaminases, should bemonitored and appropriate therapy initiated. Administer oral lead-indosing prior to administration of the Combination to help identifypatients who may be at risk of a hypersensitivity reaction.

Hepatotoxicity has been reported in a limited number of patientsreceiving cabotegravir with or without known pre-existing hepaticdisease. Hepatic adverse events have been reported in patients receivinga rilpivirine-containing tablet regimen. Patients with underlyinghepatitis B or C virus infection or marked elevations in transaminasesprior to treatment may be at increased risk for worsening or developmentof transaminase elevations. A few cases of hepatoxicity have beenreported in adult patients receiving a rilpivirine-containing regimenwho had no pre-existing hepatic disease or other identifiable riskfactors. Monitoring of liver chemistries is recommended and treatmentwith the Combination should be discontinued if hepatotoxicity issuspected.

Depressive disorders (including depressed mood, depression, dysphoria,major depression, mood altered, negative thoughts, suicide attempt, andsuicidal ideation or attempt) have been reported with rilpivirine.Promptly evaluate patients with severe depressive symptoms to assesswhether the symptoms are related to the Combination and to determinewhether the risks of continued therapy outweigh the benefits.

The concomitant use of the Combination and other drugs may result inknown or potentially significant drug interactions, some of which maylead to loss of therapeutic effect of the Combination and possibledevelopment of viral resistance.

Rilpivirine at the recommended dose of 25 mg once daily is notassociated with a clinically relevant effect on QTc. Rilpivirine plasmaconcentrations after rilpivirine injections are comparable to thoseduring therapy which do not prolong the QTc interval. In healthysubjects, 75 mg once daily and 300 mg once daily of oral rilpivirinehave been shown to prolong the QTc interval of the electrocardiogram.The Combination should be used with caution in combination with drugsthat are known to have a risk of Torsade de Pointes.

See Table 5 for steps to prevent or manage these possible and knownsignificant drug interactions, including dosing recommendations.Consider the potential for drug interactions prior to and during therapywith the Combination; review concomitant medications during therapy withthe Combination.

Residual concentrations of cabotegravir and rilpivirine may remain inthe systemic circulation of patients for prolonged periods (up to 12months or longer). Consider the long-acting characteristics ofcabotegravir and rilpivirine when the Combination is discontinued.

To minimize the risk of developing viral resistance, it is essential toadopt an alternative, fully suppressive antiretroviral regimen no laterthan 1 month after the final injection doses of the Combination. Ifvirologic failure is suspected, prescribe an alternative regimen as soonas possible.

According to another aspect of the main embodiment, because clinicaltrials are conducted under widely varying conditions, adverse reactionrates observed in the clinical trials of a drug cannot be directlycompared with rates in the clinical trials of another drug and may notreflect rates observed in practice.

The safety assessment of the Combination is based on the analysis ofpooled 48-week data from 1,182 virologically suppressed subjects withHIV-1 infection in 2 international, multicenter, open-label pivotaltrials, FLAIR and ATLAS. Additional safety information from earlierclinical trials in the cabotegravir and rilpivirine program have beenconsidered in assessing the overall safety profile of the Combination.

Adverse reactions were reported following exposure to the Combinationextended-release injectable suspensions (median time exposure: 54 weeks)and data from cabotegravir tablets and rilpivirine tablets administeredin combination as oral lead-in therapy (median time exposure: 5.3weeks). Adverse reactions include those attributable to both the oraland injectable formulations of cabotegravir and rilpivirine administeredas a combination regimen.

The most common adverse reactions regardless of severity reported in ≥2%of adult subjects in the pooled analyses from FLAIR and ATLAS arepresented in Table 3. No adverse reactions of Grade 5 occurred insubjects treated with cabotegravir plus rilpivirine. Selected laboratoryabnormalities are included in Table 4.

Non-injection-site-related adverse events leading to discontinuation andoccurring in more than 1 subject were hepatitis A, acute hepatitis B,headache, and diarrhea which occurred with an incidence of ≤1%.

TABLE 3 Adverse Reactions^(a) (Grades 1 to 4) Reported in at Least 2% ofVirologically Suppressed Subjects with HIV-1 Infection in FLAIR andATLAS Trials (Week 48 Pooled Analyses) Cabotegravir plus CurrentAntiretroviral Rilpivirine (n = 591) Regimen (n = 591) All At Least AllAt Least Adverse Reactions Grades Grade 2 Grades Grade 2 Injection sitereactions^(b) 81% 37% 0 0 Pyrexia^(c)  8%  2% 0 0 Fatigue^(d)  5%  1%<1% <1% Headache  4% <1% <1% <1% Musculoskeletal pain^(e)  3%  1% <1% 0Nausea  3% <1%  1% <1% Sleep disorders^(f)  2% <1% <1% 0 Dizziness  2%<1% <1% 0 ^(a)Adverse reactions defined as “treatment-related” asassessed by the investigator. ^(b)See below for additional informationon injection site reactions. ^(c)Pyrexia: includes pyrexia, feeling hot,chills, influenza-like illness, body temperature increased. ^(d)Fatigue:includes fatigue, malaise, asthenia. ^(e)Musculoskeletal pain: includesmusculoskeletal pain, musculoskeletal discomfort, back pain, myalgia,pain in extremity. ^(f)Sleep disorders: includes insomnia, poor qualitysleep, somnolence.

The following adverse reactions (Grades 2 to 4) occurred in <1% ofsubjects receiving cabotegravir plus rilpivirine: GastrointestinalDisorders: Abdominal pain (including upper abdominal pain), diarrhea,flatulence, nausea, vomiting, General Disorders and Administration SiteConditions: Asthenia, fatigue, malaise, Hepatobiliary Disorders:Hepatotoxicity. No cases of hepatotoxicity were observed in the pivotalPhase 3 trials. Cases were identified with cabotegravir in Phase 1 and 2trials, Investigations: Weight increase. At Week 48, subjects in FLAIRand ATLAS who received cabotegravir plus rilpivirine had a median weightgain of 1.5 kg; those in the current antiretroviral regimen group had amedian weight gain of 1.0 kg (pooled analysis). In the individual FLAIRand ATLAS trials, the median weight gain in subjects receivingcabotegravir plus rilpivirine were 1.3 kg and 1.8 kg respectively,compared with 1.5 kg and 0.3 kg in subjects receiving currentantiretroviral regimen, Musculoskeletal and Connective Tissue Disorders:Myalgia, Nervous System Disorders: Dizziness, headache, PsychiatricDisorders: Anxiety, depression, insomnia, Skin and Subcutaneous TissueDisorders: Rash (including rash erythematous, rash generalized, rashmacular, rash maculo-papular, rash morbilliform, rash papular, rashpruritic). The following Grade 1 adverse reactions occurred in subjectsreceiving cabotegravir plus rilpivirine: Nervous System Disorders:Somnolence (<1%), Psychiatric Disorders: Abnormal dreams (1%).

Local ISRs (injection site reactions) were the most frequent adverseevents associated with the intramuscular administration of theCombination. After 14,682 injections, 3,663 ISRs were reported. Thepercentage of subjects reporting ISRs decreased over time (Week 4, 70%and Week 48, 16%). A total of 1% of subjects in FLAIR and ATLASdiscontinued treatment with the Combination because of ISRs. In FLAIRand ATLAS at the Week 48 analysis, 84% of subjects had at least 1 localISR at some point over the analysis period, consisting primarily oflocalized pain/discomfort (79%); based on all grades irrespective ofrelatedness. Other manifestations of ISRs reported in more than 1% ofsubjects over the duration of the analysis period included nodules(14%), induration (12%), swelling (8%), erythema (4%), pruritus (4%),bruising (3%), warmth (2%), and hematoma (2%). Abscess and cellulitis atthe injection site were each reported in <1% of subjects. The severityof ISRs was generally mild (Grade 1, 75%) or moderate (Grade 2, 36%).Four percent (4%) of subjects experienced severe (Grade 3) ISRs, and nosubjects experienced Grade 4 ISRs. The median duration of ISR events was3 days. The percentage of subjects reporting ISRs decreased over time(Week 4, 70% and Week 48, 16%).

Selected laboratory abnormalities with a worsening grade from baselineand representing the worst-grade toxicity are presented in Table 4.

TABLE 4 Selected Laboratory Abnormalities (Grades 3 to 4; Week 48 PooledAnalyses) in FLAIR and ATLAS Trials Cabotegravir plus CurrentAntiretroviral Laboratory Parameter Rilpivirine Regimen Preferred Term(n = 591) (n = 591) ALT (>5.0 × ULN) 2% <1% AST (>5.0 × ULN) 2% <1%Bilirubin (>2.5 × ULN) <1%  <1% Creatine phosphokinase 8%  4% (≥10.0 ×ULN) Lipase (>3.0 × ULN) 5%  3% ULN = Upper limit of normal.Changes in Transaminases: A few subjects had transaminase elevationsattributed to suspected hepatotoxicity in relation to oral cabotegravirexposure in Phase 1 and 2 trials. Elevated transaminases (AST/ALT) wereobserved in subjects receiving cabotegravir plus rilpivirine during thepivotal Phase 3 trials; however, the primary reason for these elevationswas the occurrence of acute viral hepatitis (Hepatitis A, B, or C).Changes in Total Bilirubin: Small, non-progressive increases in totalbilirubin (without clinical jaundice) were observed with cabotegravirplus rilpivirine. These changes are not considered clinically relevantas they likely reflect competition between cabotegravir and unconjugatedbilirubin for a common clearance pathway (UGT1A1).Changes in Creatine Phosphokinase (CPK): Asymptomatic CPK elevations,mainly in association with exercise, have also been reported withcabotegravir plus rilpivirine.

The following adverse reactions have been identified duringpostmarketing experience in patients receiving an oralrilpivirine-containing regimen. Because these reactions are reportedvoluntarily from a population of uncertain size, it is not alwayspossible to reliably estimate their frequency or establish a causalrelationship to drug exposure: Severe skin and hypersensitivityreactions, including DRESS.

According to another aspect of the main embodiment, coadministration ofthe Combination with other medications should be monitored or avoided.

Because the Combination is a complete regimen, coadministration withother antiretroviral medications for the treatment of HIV-1 infection isnot recommended. There are no limitations on the use of otherantiretroviral medications after discontinuing the Combination.

Cabotegravir is primarily metabolized by UGT1A1 with some contributionfrom UGT1A9. Drugs which are strong inducers of UGT1A1 or 1A9 areexpected to decrease cabotegravir plasma concentrations and may resultin loss of virologic response; therefore, coadministration with thesedrugs is contraindicated. Simulations using physiologically basedpharmacokinetic (PBPK) modeling show that no clinically significantinteraction is expected during coadministration of cabotegravir withdrugs that inhibit these enzymes.

Cabotegravir is a substrate of breast cancer resistance protein (BCRP)and P-glycoprotein (P-gp) in vitro; however, because of its highpermeability, no alteration in cabotegravir absorption is expected whencoadministered with BCRP or P-gp inhibitors.

Rilpivirine is primarily metabolized by CYP3A, and drugs that induce orinhibit CYP3A may affect the clearance of rilpivirine. Coadministrationof the Combination and drugs that induce CYP3A may result in decreasedplasma concentrations of rilpivirine and loss of virologic response andpossible resistance to rilpivirine or to the class of non-nucleosidereverse transcriptase inhibitors (NNRTIs). Coadministration of theCombination and drugs that inhibit CYP3A may result in increased plasmaconcentrations of rilpivirine.

QT-Prolonging Drugs: Oral rilpivirine at the recommended dose of 25 mgonce daily is not associated with a clinically relevant effect on QTc.Plasma rilpivirine concentrations after rilpivirine injections arecomparable to those during rilpivirine therapy. In healthy subjects,75-mg and 300-mg once daily oral doses of rilpivirine have been shown toprolong the QTc interval of the electrocardiogram. The Combinationshould be used with caution in combination with drugs with a known riskof Torsade de Pointes.

Information regarding potential drug interactions with cabotegravir andrilpivirine are provided in Table 5. These recommendations are based oneither drug interaction trials following oral administration of theindividual components or predicted interactions due to the expectedmagnitude of the interaction and potential for loss of efficacy.

TABLE 5 Established and Other Potentially Significant Drug InteractionsConcomitant Drug Class: Effect on Drug Name Concentration ClinicalComment Anticonvulsants: ↓Cabotegravir Coadministration is Carbamazepine↓Rilpivirine contraindicated with the Oxcarbazepine combination due topotential Phenobarbital for loss of therapeutic effect Phenytoin anddevelopment of resistance Antimy cobacterials: ↓Cabotegravir [seeContraindications (4)]. Rifampin^(a) ↓Rilpivirine Rifapentine Antimycobacterial: ↓Cabotegravir Rifabutin^(a) ↔Rifabutin ↓RilpivirineGlucocorticoid (systemic): ↓Rilpivirine Dexamethasone (more than asingle-dose treatment) Herbal Product: ↓Rilpivirine St John’s wort(Hypericum perforatum) Macrolide or ketolide ↔Cabotegravir Wherepossible, consider antibiotics: ↑Rilpivirine alternatives, such asClarithromycin azithromycin. Erythromycin Telithromycin Narcoticanalgesic: ↔Cabotegravir No dose adjustment is required Methadone³↓Methadone when starting coadministration ↔Rilpivirine of methadone withthe combination. However, clinical monitoring is recommended asmethadone maintenance therapy may need to be adjusted in some patients.↑= Increase, ↓= Decrease, ↔= No change.

Based on drug interaction study results, the following drugs can becoadministered with cabotegravir without a dose adjustment: etravirine,midazolam, oral contraceptives containing levonorgestrel and ethinylestradiol, and rilpivirine.

Based on drug interaction study results, the following drugs can becoadministered with rilpivirine: acetaminophen, atorvastatin,cabotegravir, chlorzoxazone, dolutegravir, ethinyl estradiol,norethindrone, raltegravir, ritonavir-boosted atazanavir,ritonavir-boosted darunavir, sildenafil, tenofovir alafenamide, andtenofovir disoproxil fumarate. Rilpivirine did not have a clinicallysignificant effect on the pharmacokinetics of digoxin or metformin. Noclinically relevant drug-drug interaction is expected when rilpivirineis coadministered with maraviroc, ribavirin, or the nucleoside reversetranscriptase inhibitors (NRTIs) abacavir, emtricitabine, lamivudine,stavudine, and zidovudine.

According to another aspect of the main embodiment, care should be takenwith administration of the Combination to specific patient populations.

There is a pregnancy exposure registry that monitors pregnancy outcomesin women exposed to the Combination during pregnancy. There areinsufficient human data on the use of the Combination during pregnancyto adequately assess a drug-associated risk of birth defects andmiscarriage. Cabotegravir use in pregnant women has not been evaluated;however, rilpivirine use during pregnancy has been evaluated in over 200first trimester exposures reported to the APR (Antiretroviral PregnancyRegister). Available data from the APR show no increase in the risk ofoverall major birth defects with exposure to rilpivirine during thefirst trimester of pregnancy compared with the background rate for majorbirth defects of 2.7% in a U.S. reference population of the MetropolitanAtlanta Congenital Defects Program (MACDP).

The rate of miscarriage is under-reported in the APR. The backgroundrisk for major birth defects and miscarriage for the indicatedpopulation is unknown. The estimated background rate of miscarriage inclinically recognized pregnancies in the U.S. general population is 15%to 20%. The APR uses the MACDP as the U.S. reference population forbirth defects in the general population. The MACDP evaluates women andinfants from a limited geographic area and does not include outcomes forbirths that occurred at less than 20 weeks' gestation.

Cabotegravir and rilpivirine have been detected in systemic circulationfor up to 12 months or longer after discontinuing injections of theCombination; therefore, consideration should be given to the potentialfor fetal exposure during pregnancy.

In animal reproduction studies, no evidence of adverse developmentaloutcomes was observed with oral cabotegravir in rats (>30 times theexposure at the maximum recommended human dose [MRHD] of 30 mg/day oforal cabotegravir or the 400-mg intramuscular injection dose) or inrabbits (exposure 0.66 times the MRHD of 30 mg/day of oral cabotegraviror exposure ˜1 times the 400-mg intramuscular injection dose). Likewise,with oral rilpivirine, there were no adverse outcomes at exposures ≥12(rats) and ≥57 (rabbits) times the exposure at the MRHD of 25 mg oncedaily of oral rilpivirine and of 600-mg intramuscular injection dose ofrilpivirine.

Lower exposures with oral rilpivirine were observed during pregnancy.Viral load should be monitored closely if the patient remains on theCombination during pregnancy.

Human Data: Rilpivirine: Based on prospective reports to the APR of 524exposures to oral rilpivirine during pregnancy resulting in live births,there was no difference between the overall risk of birth defects forrilpivirine compared with the background birth defect rate of 2.7% inthe U.S. reference population of the MACDP. The prevalence of birthdefects in live births was 0.9% (95% CI: 0.2% to 2.5%) and 1.24% (95%CI: 0.1% to 4.1%) following first and second/third trimester exposure,respectively, to rilpivirine-containing regimens. In a clinical trial,total oral rilpivirine exposures were generally lower during pregnancycompared with the postpartum period.

Animal Data: Cabotegravir: In a prenatal and postnatal development studyin rats, cabotegravir was administered orally at 0.5, 5, or 1,000mg/kg/day during organogenesis and through delivery and lactation. At1,000 mg/kg/day (>30 times the systemic exposure at the MRHD of 30mg/day dosed orally or the 400-mg intramuscular injection dose),cabotegravir delayed the onset of parturition, and in some rats, thisdelay was associated with an increased number of stillbirths andneonatal mortalities immediately after birth. There were no alterationsto growth and development of surviving offspring at doses up to 1,000mg/kg/day. When rat pups born to cabotegravir-treated dams werecross-fostered at birth and nursed by control mothers, similarincidences of neonatal mortalities were observed; there was no effect onneonatal survival of control pups nursed from birth bycabotegravir-treated mothers. A lower dose of 5 mg/kg/day ofcabotegravir (exposure [AUC] >10 times the MRHD of 30 mg/day dosedorally or the 400-mg intramuscular injection dose) was not associatedwith delayed parturition or neonatal mortality in rats. Whencabotegravir was administered orally to pregnant rats and rabbits (dosesof 1,000 or 2,000 mg/kg/day, respectively) during organogenesis, therewas no effect on survival when fetuses were delivered by cesareansection. No adverse effects on embryo-fetal development were observed inrabbit fetuses up to 2,000 mg/kg/day (exposure [AUC] 0.66 times the MRHDof 30 mg/day dosed orally or ˜1 times the 400-mg intramuscular injectiondose); in rats, alterations in fetal growth (decreased body weights) inthe presence of maternal toxicity (decreased body weight gain, transientreductions in food consumption) were observed at 1,000 mg/kg/day (>30times the systemic exposure at the MRHD of 30 mg/day dosed orally or the400-mg intramuscular injection dose); however, there were no testarticle-related fetal malformations or variations at any dose. Studiesin pregnant rats showed that cabotegravir crosses the placenta and canbe detected in fetal tissue.

Rilpivirine: Rilpivirine was administered orally to pregnant rats (40,120, or 400 mg/kg/day) and rabbits (5, 10, or 20 mg/kg/day) throughorganogenesis (on Gestation Days 6 through 17, and 6 through 19,respectively). No significant toxicological effects were observed inembryo-fetal toxicity studies performed with rilpivirine in rats andrabbits at exposures ≥12 (rats) and ≥57 (rabbits) times the exposure inhumans at the MRHD of 25 mg once daily or 600-mg intramuscular injectiondose of rilpivirine in HIV-1-infected patients. In a prenatal andpostnatal development study with rilpivirine, where rats wereadministered up to 400 mg/kg/day through lactation, no significantadverse effects directly related to drug were noted in the offspring.

The Centers for Disease Control and Prevention recommends thatHIV-1-infected mothers in the United States not breastfeed their infantsto avoid risking postnatal transmission of HIV-1 infection. It is notknown if the components of the Combination are present in human breastmilk, affect human milk production, or have effects on the breastfedinfant. When administered to lactating rats, cabotegravir andrilpivirine were present in milk. Cabotegravir and rilpivirine could bepresent in human milk for 12 months or longer after the last injectionshave been administered.

Because of the potential for (1) HIV-1 transmission (in HIV-negativeinfants), (2) developing viral resistance (in HIV-positive infants), and(3) adverse reactions in a breastfed infant similar to those seen inadults, instruct mothers not to breastfeed if they are receiving theCombination.

Animal Data: Cabotegravir: In animals, no studies have been conducted toassess the secretion of cabotegravir into milk directly; however,cabotegravir was present in plasma of rat pups exposed through the milkof lactating rats (dosed up to 1,000 mg/kg/day), with mean plasmaconcentrations in pups of approximately 70% that of plasmaconcentrations occurring in pregnant female rats on Gestation Day 20.

Rilpivirine: In animals, no studies have been conducted to assess thesecretion of rilpivirine into milk directly; however, rilpivirine waspresent in plasma of rat pups exposed through the milk of lactating rats(dosed up to 400 mg/kg/day).

Safety and efficacy of the components of the Combination have not beenestablished in pediatric patients.

Clinical trials of the Combination did not include sufficient numbers ofsubjects aged 65 and older to determine whether they respond differentlyfrom younger subjects. In general, caution should be exercised inadministration of the Combination in elderly patients reflecting greaterfrequency of decreased hepatic, renal, or cardiac function, and ofconcomitant disease or other drug therapy.

The Combination has not been studied in patients with renal impairment.Based on studies with oral cabotegravir and population pharmacokineticanalyses of oral rilpivirine, no dosage adjustment of the Combination isnecessary for patients with mild or moderate renal impairment(creatinine clearance ≥30 mL/min) and not on dialysis. However, inpatients with severe renal impairment (creatinine clearance <30 mL/min)or end-stage renal disease, the Combination should be used with cautionand increased monitoring for adverse effects is recommended.

The Combination has not been studied in patients with hepaticimpairment. Based on separate studies with oral cabotegravir and oralrilpivirine, no dosage adjustment of the Combination is necessary forpatients with mild or moderate hepatic impairment (Child-Pugh Score A orB). The effect of severe hepatic impairment (Child-Pugh Score C) on thepharmacokinetics of cabotegravir or rilpivirine is unknown.

According to another aspect of the main embodiment, a treatment foroverdosage of one or both components of the Combination is provided.There is no known specific treatment for overdose with cabotegravir orrilpivirine. If overdose occurs, the patient should be monitored andstandard supportive treatment applied as required, including monitoringof vital signs and ECG (QT interval) as well as observation of theclinical status of the patient. As both cabotegravir and rilpivirine arehighly bound to plasma proteins, it is unlikely that either would besignificantly removed by dialysis. Consider the prolonged exposure tocabotegravir and rilpivirine (components of the Combination) followingan injection when assessing treatment needs and recovery.

According to another aspect of the main embodiment, the Combinationcontains cabotegravir extended-release injectable suspension, an HIVINSTI, co-packaged with and rilpivirine extended-release injectablesuspension, an HIV NNRTI, in particular the Combination containscabotegravir extended-release injectable suspension, an HIV INSTI,co-packed with rilpivirine extended-release injectable suspension, anHIV NNRTI. In an embodiment, the Combination contains cabotegravirextended-release injectable suspension, an HIV INSTI, packed separatelyfrom the rilpivirine extended-release injectable suspension, an HIVNNRTI.

Cabotegravir: The chemical name for cabotegravir is(3S,11aR)—N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide.The empirical formula is C₁₉H₁₇F₂N₃O₅ and the molecular weight is 405.35g/mol. It has the following structural formula:

Cabotegravir extended-release injectable suspension is a white to lightpink free-flowing suspension for intramuscular injection. Each sterilesingle-dose vial contains the following:

2-mL Vial

Cabotegravir 400 mg and the following inactive ingredients: mannitol (70mg), polysorbate 20 (40 mg), polyethylene glycol (PEG) 3350 (40 mg), andWater for Injection.

3-mL Vial

Cabotegravir 600 mg and the following inactive ingredients: mannitol(105 mg), polysorbate 20 (60 mg), polyethylene glycol (PEG) 3350 (60mg), and Water for Injection.The cabotegravir tablet contains cabotegravir, as cabotegravir sodium.Cabotegravir sodium is a white to almost white solid that is slightlysoluble in water. Each immediate-release film-coated tablet ofcabotegravir for oral administration contains 30 mg of cabotegravir(equivalent to 31.62 mg cabotegravir sodium) and the inactiveingredients: hypromellose, lactose monohydrate, magnesium stearate,microcrystalline cellulose, and sodium starch glycolate. The tabletfilm-coating contains hypromellose, polyethylene glycol, and titaniumdioxide.Rilpivirine: The chemical name for rilpivirine is4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile.Its molecular formula is C₂₂H₁₈N₆ and its molecular weight is 366.42.Rilpivirine has the following structural formula:

Rilpivirine extended-release injectable suspension is a white tooff-white suspension for intramuscular injection. Each sterilesingle-dose vial contains the following:

2-mL Vial

Rilpivirine 600 mg and the following inactive ingredients: poloxamer 338(100 mg), citric acid monohydrate (2 mg); glucose monohydrate, sodiumdihydrogen phosphate monohydrate, sodium hydroxide to adjust pH andensure isotonicity, and Water for Injection.

3-mL Vial

Rilpivirine 900 mg and the following inactive ingredients: poloxamer 338(150 mg), citric acid monohydrate (3 mg); glucose monohydrate, sodiumdihydrogen phosphate monohydrate, sodium hydroxide to adjust pH andensure isotonicity, and Water for Injection.The vial stoppers are not made with natural rubber latex.

According to another aspect of the main embodiment, the Combinationexhibits certain clinical pharmacology.

The effect of the Combination on QT interval has not been studied.

Cabotegravir: In a randomized, placebo-controlled, 3-period cross-overtrial, 42 healthy subjects were randomized into 6 random sequences andreceived 3 oral doses of placebo, cabotegravir 150 mg every 12 hours(C_(max) approximately 3-fold of the 30-mg once-daily dose), and asingle dose of moxifloxacin 400 mg (active control). After baseline andplacebo adjustment, the maximum time-matched mean QTc change based onFridericia's correction method (QTcF) for cabotegravir was 2.62 msec(1-sided 95% upper CI: 5.26 msec). Cabotegravir did not prolong the QTcinterval over 24 hours post dose.Rilpivirine: The effect of rilpivirine at the recommended oral dose of25 mg once daily on the QTcF interval was evaluated in a randomized,placebo- and active- (moxifloxacin 400 mg once daily) controlledcrossover trial in 60 healthy adults, with 13 measurements over 24 hoursat steady state. The maximum mean time-matched (95% upper confidencebound) differences in QTcF interval from placebo after baselinecorrection was 2.0 (5.0) msec (i.e., below the threshold of clinicalconcern). When 75-mg and 300-mg once daily oral doses of rilpivirine (3times and 12 times the recommended oral dosage, respectively) werestudied in healthy adults, the maximum mean time-matched (95% upperconfidence bound) differences in QTcF interval from placebo afterbaseline correction were 10.7 (15.3) and 23.3 (28.4) msec, respectively.Steady-state administration of rilpivirine 75 mg once daily and 300 mgonce daily resulted in a mean steady-state C_(max) approximately4.4-fold and 11.6-fold, respectively, higher than the mean steady-stateC_(max) observed with the recommended 600-mg monthly dose of rilpivirineextended-release injectable suspension.

The pharmacokinetic properties of the components of the Combination areprovided in Table 6. The multiple-dose pharmacokinetic parameters areprovided in Table 7.

TABLE 6 Pharmacokinetic Properties of the Components of the CombinationCabotegravir Rilpivirine Absorption Tmax (days), median 7 3 to 4Distribution % Bound to human >99.8 99.7 plasma proteins Blood-to-plasmaratio 0.5 0.7 Elimination t_(1/2) (weeks) (absorption rate 5.6 to 11.513 to 28 limited), mean Metabolism Metabolic pathways UGT1A1 CYP3AUGT1A9 (minor) Excretion Major route of elimination MetabolismMetabolism % of dose excreted as total ¹⁴C 27 (0)  6 (<1) (unchangeddrug) in urine^(a) % of dose excreted as total ¹⁴C 59 (47) 85 (26)(unchanged drug) in feces^(a) ^(a)Dosing in mass balance studies:single-dose oral administration of [¹⁴C] cabotegravir; single-dose oraladministration of [¹⁴C] rilpivirine.

TABLE 7 Multiple-Dose Pharmacokinetic Parameters following MonthlyIntramuscular Injections of the Components of the Combination Drug DoseGeometric Mean (95% CI)^(a) Cabotegravir 400-mg AUC_(tau) C_(max)C_(trough) monthly IM (mcg · h/mL) (mcg/mL) (mcg/mL) injection 2,461 4.22.9 (2,413, 2,510) (4.1, 4.3) (2.9, 3.0) Rilpivirine 600-mg AUC_(tau)C_(max) C_(trough) monthly IM (ng · h/mL) (ng/mL) (ng/mL) injection65,603 116 82.2 (63,756, 67,503) (113, 119) (79.9, 84.6)^(a)Pharmacokinetic parameter values were based on individual post-hocestimates from separate cabotegravir and rilpivirine populationpharmacokinetic models for subjects enrolled in FLAIR and ATLAS.

Cerebrospinal Fluid (CSF): Cabotegravir is present in CSF. InHIV-1-infected subjects receiving both cabotegravir extended-releaseinjectable suspension and rilpivirine extended-release injectablesuspension, the median cabotegravir CSF-to-plasma concentration ratio(n=16) was 0.304 to 0.344 (range: 0.218 to 0.449) and higher thancorresponding median unbound cabotegravir concentrations in plasma 1week following steady-state cabotegravir and rilpivirineextended-release injectable suspensions given monthly or every 2 months.Rilpivirine is present in CSF. In the same 16 subjects, the medianrilpivirine CSF-to-plasma ratio was 1.07 to 1.32% (range: notquantifiable to 1.69%). Consistent with therapeutic cabotegravir andrilpivirine concentrations in the CSF, CSF HIV-1 RNA concentrations(n=16) were <50 copies/mL in 100% and <2 copies/mL in 15/16 (94%) ofsubjects. At the same time point, plasma HIV-1 RNA concentrations (n=18)were <50 copies/mL in 100% and <2 copies/mL in 12/18 (66.7%) ofsubjects.

According to another aspect of the main embodiment, pharmacokineticsvaries by specific patient populations.

Pediatric Patients: The pharmacokinetics of the components of thecombination have not been studied in pediatric patients.Geriatric Patients: Population pharmacokinetic analyses indicated agehad no clinically relevant effect on the pharmacokinetics ofcabotegravir or rilpivirine. Pharmacokinetic data in subjects aged 65years and older are limited.Patients with Renal Impairment: No clinically important pharmacokineticdifferences between subjects with severe renal impairment (CrCL <30mL/min and not on dialysis) and matching healthy subjects were observedwith oral cabotegravir. No dosage adjustment is necessary for patientswith mild to severe renal impairment (not on dialysis). Cabotegravir hasnot been studied in patients requiring dialysis.Population pharmacokinetic analyses indicated that mild renal impairmenthad no clinically relevant effect on the exposure of oral rilpivirine.There is limited or no information regarding the pharmacokinetics ofrilpivirine in patients with moderate or severe renal impairment,end-stage renal disease, or patients requiring dialysis.Patients with Hepatic Impairment: No clinically importantpharmacokinetic differences between subjects with moderate hepaticimpairment and matching healthy subjects were observed with oralcabotegravir. No dosage adjustment is necessary for patients with mildto moderate hepatic impairment (Child-Pugh Score A or B). The effect ofsevere hepatic impairment (Child-Pugh Score C) on the pharmacokineticsof cabotegravir has not been studied.Rilpivirine exposure was 47% higher in subjects (n=8) with mild hepaticimpairment (Child-Pugh Score A) and 5% higher in subjects (n=8) withmoderate hepatic impairment (Child-Pugh Score B) compared with matchedcontrols. The effect of severe hepatic impairment (Child-Pugh Score C)on the pharmacokinetics of rilpivirine has not been studied.Patients with HBV/HCV Co-infection: Cabotegravir plus rilpivirine hasnot been studied in patients with hepatitis B co-infection. There islimited experience in patients with hepatitis C co-infection receivingcabotegravir and rilpivirine.Gender and Race: Population pharmacokinetic analyses revealed thatgender and race had no clinically relevant effect on thepharmacokinetics of cabotegravir or rilpivirine.Polymorphisms in Drug Metabolizing Enzymes: In a meta-analysis ofhealthy and HIV-1-infected subject trials, HIV-infected subjects withUGT1A1 genotypes conferring poor cabotegravir metabolism had a 1.2-foldincrease in mean steady-state cabotegravir AUC, C_(max), and C_(tau)following cabotegravir long-acting injection compared with subjects withgenotypes associated with normal metabolism via UGT1A1. No doseadjustment is required in subjects with UGT1A1 polymorphisms.Body Mass Index (BMI): Population pharmacokinetic analyses revealed noclinically relevant effect of BMI on the exposure of cabotegravir andrilpivirine; therefore, no dose adjustment is required on the basis ofBMI. Consider the BMI of the patient to ensure that the needle length issufficient to reach the gluteus muscle.

According to another aspect of the main embodiment, drug interactionstudies were conducted with oral cabotegravir or oral rilpivirine, asindividual components, and other drugs likely to be coadministered orcommonly used as probes for pharmacokinetic interactions.

Cabotegravir is not a clinically relevant inhibitor of the followingenzymes and transporters: CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and3A4; UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7, 2B15, and 2B17; P-gp; BCRP;bile salt export pump (BSEP); organic cation transporter (OCT)1, OCT2;organic anion transporter polypeptide (OATP)1B1, OATP1B3; multidrug andtoxin extrusion transporter (MATE) 1, MATE 2-K; multidrug resistanceprotein (MRP)2 or MRP4.In vitro, cabotegravir inhibited renal organic anion transporters (OAT)1(IC₅₀=0.81 microM) and OAT3 (IC₅₀=0.41 microM). However, based on PBPKmodeling, no interaction with OAT substrates is expected at clinicallyrelevant concentrations.

In vitro, cabotegravir did not induce CYP1A2, CYP2B6, or CYP3A4. Basedon these data and the results of drug interaction trials, cabotegraviris not expected to affect the pharmacokinetics of drugs that aresubstrates of these enzymes.

Rilpivirine is primarily metabolized by CYP3A. Rilpivirine injection isnot likely to have a clinically relevant effect on the exposure of drugsmetabolized by CYP enzymes.

Based on their in vitro and clinical drug interaction profiles,cabotegravir and rilpivirine are not expected to alter concentrations ofother antiretroviral medications including protease inhibitors, NRTIs,NNRTIs, integrase inhibitors, entry inhibitors, and ibalizumab.

Cabotegravir is primarily metabolized by UGT1A1 with some contributionfrom UGT1A9. Drugs which are strong inducers of UGT1A1 or 1A9 areexpected to decrease cabotegravir plasma concentrations leading to lackof efficacy; therefore, coadministration with these drugs iscontraindicated.

In vitro, cabotegravir was not a substrate of OATP1B1, OATP1B3, or OCT1.Cabotegravir is a substrate of P-gp and BCRP in vitro; however, becauseof its high permeability, no alteration in cabotegravir absorption isexpected with coadministration of P-gp or BCRP inhibitors.

The effects of cabotegravir or rilpivirine on the exposure ofcoadministered drugs are summarized in Tables 8 and 10 and the effectsof coadministered drugs on the exposure of cabotegravir or rilpivirineare summarized in Tables 9 and 11, respectively. No drug interactionstudies have been performed with cabotegravir or rilpivirineextended-release suspension for injection. The drug interaction dataprovided is obtained from studies with oral cabotegravir or oralrilpivirine. Dosing recommendations as a result of established and otherpotentially significant drug-drug interactions with cabotegravir andrilpivirine are provided in Table 5.

TABLE 8 Effect of Cabotegravir on the Pharmacokinetics of CoadministeredDrugs Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters ofCoadministered Coadministered Drug with/without Cabotegravir Drug(s)Dose of No Effect = 1.00 and Dose(s) Cabotegravir n C_(max) AUC C_(τ) orC₂₄ Ethinyl estradiol 30 mg 19 0.92 1.02 1.00 0.03 mg once daily oncedaily (0.83, 1.03) (0.97, 1.08) (0.92, 1.10) Levonorgestrel 30 mg 191.05 1.12 1.07 0.15 mg once daily once daily (0.96, 1.15) (1.07, 1.18)(1.01, 1.15) Midazolam 30 mg 12 1.09 1.10 NA 3 mg once daily (0.94,1.26) (0.95, 1.26) Rilpivirine 30 mg 11 0.96 0.99 0.92 25 mg once dailyonce daily (0.85, 1.09) (0.89, 1.09) (0.79, 1.07) CI = ConfidenceInterval; n = Maximum number of subjects with data; NA = Not available.

TABLE 9 Effect of Coadministered Drugs on the Pharmacokinetics ofCabotegravir Geometric Mean Ratio (90% CI) of CabotegravirPharmacokinetic Coadministered Parameters with/without CoadministeredDrugs Drug(s) Dose of No Effect = 1.00 and Dose(s) Cabotegravir nC_(max) AUC C_(τ) or C₂₄ Etravirine 30 mg 12 1.04 1.01 1.00 200 mg twicedaily once daily (0.99, 1.09) (0.96, 1.06) (0.94, 1.06) Rifabutin 30 mg12 0.83 0.77 0.74 300 mg once daily once daily (0.76, 0.90) (0.74, 0.83)(0.70, 0.78) Rifampin 30 mg 15 0.94 0.41 NA 600 mg once daily singledose (0.87, 1.02) (0.36, 0.46) Rilpivirine 30 mg 11 1.05 1.12 1.14 25 mgonce daily once daily (0.96, 1.15) (1.05, 1.19) (1.04, 1.24) CI =Confidence Interval; n = Maximum number of subjects with data; NA = Notavailable.

TABLE 10 Effect of Rilpivirine on the Pharmacokinetics of CoadministeredDrugs Geometric Mean Ratio (90% CI) of Coadministered DrugPharmacokinetic Coadministered Parameters with/without EDURANT Drug(s)Dose of No Effect = 1.00 and Dose(s) Rilpivirine n C_(max) AUC C_(min)Acetaminophen 150 mg 16 0.97 0.91 NA 500-mg single dose once daily^(a)(0.86 to 1.10) (0.86 to 0.97) Atorvastatin 150 mg 16 1.35 1.04 0.85 40mg once daily once daily^(a) (1.08 to 1.68) (0.97 to 1.12) (0.69 to1.03) 2-hydroxy-atorvastatin 1.58 1.39 1.32 (1.33 to 1.87) (1.29 to1.50) (1.10 to 1.58) 4-hydroxy-atorvastatin 1.28 1.23 NA (1.15 to 1.43)(1.13 to 1.33) Chlorzoxazone 150 mg 16 0.98 1.03 NA 500-mg single doseonce daily^(a) (0.85 to 1.13) (0.95 to 1.13) taken 2 hours afterrilpivirine Darunavir/ritonavir 150 mg 15 0.90 0.89 0.89 800/100 mg oncedaily once daily^(a) (0.81-1.00) (0.81-0.99) (0.68-1.16) Didanosine 150mg 13 0.96 1.12 NA 400 mg once daily once daily^(a) (0.80-1.14)(0.99-1.27) delayed release capsules taken 2 hours before rilpivirineDigoxin 25 mg 22 1.06 0.98 NA 0.5-mg single dose once daily (0.97 to1.17) (0.93 to 1.04)^(c) Ethinylestradiol 25 mg 17 1.17 1.14 1.09 0.035mg once daily once daily (1.06 to 1.30) (1.10 to 1.19) (1.03 to 1.16)Norethindrone 0.94 0.89 0.99 1 mg once daily (0.83 to 1.06) (0.84 to0.94) (0.90 to 1.08) Ketoconazole 150 mg 14 0.85 0.76 0.34 400 mg oncedaily once daily^(a) (0.80 to 0.90) (0.70 to 0.82) (0.25 to 0.46)Lopinavir/ritonavir 150 mg 15 0.96 0.99 0.89 400/100 mg twice daily oncedaily^(a) (0.88-1.05) (0.89-1.10) (0.73-1.08) (soft gel capsule)Methadone 25 mg 13 60-100 mg once daily, once daily individualized doseR(−) methadone 0.86 0.84 0.78 (0.78 to 0.95) (0.74 to 0.95) (0.67 to0.91) S(+) methadone 0.87 0.84 0.79 (0.78 to 0.97) (0.74 to 0.96) (0.67to 0.92) Metformin 25 mg 20 1.02 0.97 NA 850-mg single dose once daily(0.95 to -1.10) (0.90 to 1.06)^(b) Raltegravir 25 mg 23 1.10 1.09 1.27400 mg twice daily once daily (0.77-1.58) (0.81-1.47) (1.01-1.60)Rifampin 150 mg 16 1.02 0.99 NA 600 mg once daily once daily^(a) (0.93to 1.12) (0.92 to 1.07) 25-desacetylrifampin 1.00 0.91 NA (0.87 to 1.15)(0.77 to 1.07) Sildenafil 75 mg 16 0.93 0.97 NA 50-mg single dose oncedaily^(a) (0.80 to 1.08) (0.87 to 1.08) N-desmethyl-sildenafil 0.90 0.92NA (0.80 to 1.02) (0.85 to 0.99)^(c) Tenofovir disoproxil 150 mg 16 1.191.23 1.24 fumarate once daily^(a) (1.06-1.34) (1.16-1.31) (1.10-1.38)300 mg once daily CI = Confidence Interval; n = Maximum number ofsubjects with data; NA = Not available. ^(a)This interaction study hasbeen performed with a dose higher than the recommended dose forrilpivirine (25 mg once daily) assessing the maximal effect on thecoadministered drug. ^(b)n = (maximum number of subjects with data) forAUC_((0-∞)) = 15. ^(c)AUC_((0-last)).

TABLE 11 Effect of Coadministered Drugs on the Pharmacokinetics ofRilpivirine Coadministered Geometric Mean Ratio (90% CI) of RilpivirinePharmacokinetic Drug(s) Dose of Parameters with/without CoadministeredDrugs No Effect = 1.00 and Dose(s) Rilpivirine n C_(max) AUC C_(min)Acetaminophen 150 mg 16 1.09 1.16 1.26 500-mg single dose once daily^(a)(1.01 to 1.18) (1.10 to 1.22) (1.16 to 1.38) Atorvastatin 150 mg 16 0.910.90 0.90 40 mg once daily once daily^(a) (0.79 to 1.06) (0.81 to 0.99)(0.84 to 0.96) Chlorzoxazone 150 mg 16 1.17 1.25 1.18 500-mg single dosetaken once daily^(a) (1.08 to 1.27) (1.16 to 1.35) (1.09 to 1.28) 2hours after rilpivirine Darunavir/ritonavir 150 mg 14 1.79 2.30 2.78800/100 mg once daily once daily^(a) (1.56 to 2.06) (1.98 to 2.67) (2.39to 3.24) Didanosine 150 mg 21 1.00 1.00 1.00 400 mg once daily oncedaily^(a) (0.90 to 1.10) (0.95 to 1.06) (0.92 to 1.09) delayed releasecapsules taken 2 hours before rilpivirine Ethinylestradiol/  25 mg 15↔^(b) ↔^(b) ↔^(b) Norethindrone once daily 0.035 mg once daily/ 1 mgonce daily Ketoconazole 150 mg 15 1.30 1.49 1.76 400 mg once daily oncedaily^(b) (1.13 to 1.48) (1.31 to 1.70) (1.57 to 1.97)Lopinavir/ritonavir 150 mg 15 0.96 0.99 0.89 400/100 mg twice daily oncedaily^(a) (0.88 to 1.05) (0.89 to 1.10) (0.73 to 1.08) (soft gelcapsule) Methadone  25 mg 12 ↔^(b) ↔^(b) ↔^(b) 60-100 mg once daily,once daily individualized dose Raltegravir  25 mg 23 1.12 1.12 1.03 400mg twice daily once daily (1.04 to 1.20) (1.05 to 1.19) (0.96 to 1.12)Rifabutin  25 mg 18 0.69 0.58 0.52 300 mg once daily once daily (0.62 to0.76) (0.52 to 0.65) (0.46 to 0.59) Rifabutin  50 mg 18 1.43 1.16 0.93300 mg once daily once daily (1.30 to 1.56) (1.06 to 1.26) (0.85 to1.01) (reference arm for comparison was 25-mg-once- daily rilpivirineadministered alone) Rifampin 150 mg 16 0.31 0.20 0.11 600 mg once dailyonce daily^(a) (0.27 to 0.36) (0.18 to 0.23) (0.10 to 0.13) Sildenafil75 mg 16 0.92 0.98 1.04 50-mg single dose once daily^(a) (0.85 to 0.99)(0.92 to 1.05) (0.98 to 1.09) Tenofovir disoproxil 150 mg 16 0.96 1.010.99 fumarate once daily^(a) (0.81 to 1.13) (0.87 to 1.18) (0.83 to1.16) 300 mg once daily CI = Confidence Interval; n = Maximum number ofsubjects with data; NA = Not available; ↔ = No change. ^(a)Thisinteraction study has been performed with a dose higher than therecommended dose for rilpivirine (25 mg once daily) assessing themaximal effect on the coadministered drug. ^(b)Comparison based onhistoric controls.

Cabotegravir inhibits HIV integrase by binding to the integrase activesite and blocking the strand transfer step of retroviraldeoxyribonucleic acid (DNA) integration which is essential for the HIVreplication cycle. The mean 50% inhibitory concentration (IC₅₀) value ofcabotegravir in a strand transfer assay using purified recombinant HIV-1integrase was 3.0 nM.

Rilpivirine is a diarylpyrimidine NNRTI of HIV-1 and inhibits HIV-1replication by non-competitive inhibition of HIV-1 reverse transcriptase(RT). Rilpivirine does not inhibit the human cellular DNA polymerases α,β, and γ.

Cabotegravir exhibited antiviral activity against laboratory strains ofHIV-1 (subtype B, n=4) with mean 50 percent effective concentration(EC₅₀) values of 0.22 nM to 1.7 nM in peripheral blood mononuclear cells(PBMCs) and 293 cells. Cabotegravir demonstrated antiviral activity inPBMCs against a panel of 24 HIV-1 clinical isolates (3 in each of groupM subtypes A, B, C, D, E, F, and G and 3 in group O) with a median EC₅₀value of 0.19 nM (range: 0.02 nM to 1.06 nM). The median EC₅₀ valueagainst subtype B clinical isolates was 0.05 nM (range: 0.02 to 0.50 nM,n=3). Against clinical HIV-2 isolates, the median EC₅₀ value was 0.12 nM(range: 0.10 nM to 0.14 nM, n=4).

Rilpivirine exhibited activity against laboratory strains of wild-typeHIV-1 in an acutely infected T-cell line with a median EC₅₀ value forHIV-1_(IIIB) of 0.73 nM (0.27 ng/mL). Rilpivirine demonstrated antiviralactivity against a broad panel of HIV-1 group M (subtypes A, B, C, D, F,G, and H) primary isolates with EC₅₀ values ranging from 0.07 nM to 1.01nM (0.03 to 0.37 ng/mL) and was less active against group O primaryisolates with EC₅₀ values ranging from 2.88 to 8.45 nM (1.06 to 3.10ng/mL).

In cell culture, cabotegravir was not antagonistic in combination withthe NNRTI rilpivirine, or the NRTIs emtricitabine (FTC), lamivudine(3TC), or tenofovir disoproxil fumarate (TDF).

The antiviral activity of rilpivirine was not antagonistic when combinedwith the NNRTIs efavirenz, etravirine, or nevirapine; the NRTIsabacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir,or zidovudine; the protease inhibitors amprenavir, atazanavir,darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, ortipranavir; the fusion inhibitor enfuvirtide; the CCR5 co-receptorantagonist maraviroc, or the INSTI raltegravir.

Cell Culture: Cabotegravir-resistant viruses were selected duringpassage of HIV-1 strain IIIB in MT-2 cells in the presence ofcabotegravir. Amino acid substitutions in integrase which emerged andconferred decreased susceptibility to cabotegravir included Q146L (foldchange: 1.3 to 4.6), S153Y (fold change: 2.8 to 8.4), S153Y (foldchange: 6.3 to 6.4), and I162M (fold change: 2.8). The integrase (IN)substitution T124A also emerged alone (fold change: 1.1 to 7.4 incabotegravir susceptibility), in combination with S153Y (fold change:3.6 to 6.6 in cabotegravir susceptibility), or I162M (2.8-fold change incabotegravir susceptibility). Cell culture passage of virus harboringintegrase substitutions Q148H, Q148K, or Q148R selected for additionalsubstitutions (C56S, V72I, L74M, V75A, T122N, E138K, G140S, G149A, andM154I), with substituted viruses having reduced susceptibility tocabotegravir of 2.0- to 410-fold change. The combinations of E138K+Q148Kand V72I+E138K+Q148K conferred the greatest reductions of 53- to260-fold and 410-fold change, respectively.

Rilpivirine-resistant strains were selected in cell culture startingfrom wild-type HIV-1 of different origins and subtypes as well asNNRTI-resistant HIV-1. The frequently observed amino acid substitutionsthat emerged and conferred decreased phenotypic susceptibility torilpivirine included L100I; K101E; V106I and A; V108I; E138K and G, Q,R; V179F and I; Y181C and I; V189I; G190E; H221Y; F227C; and M230I andL.

Clinical Trials: In the pooled Phase 3 FLAIR and ATLAS trials, therewere 7 confirmed virologic failures (2 consecutive HIV-1 RNA >200copies/mL) on cabotegravir plus rilpivirine (7/591, 1.2%) and 7confirmed virologic failures on current antiretroviral regimen (CAR)(7/591, 1.2%). Of the 7 virologic failures in the cabotegravir plusrilpivirine arm, 6 had post-baseline resistance data. All 6 hadon-treatment rilpivirine resistance-associated substitutions K101E,E138A, or E138K in reverse transcriptase, and 5 of them showed reducedphenotypic susceptibility to rilpivirine (range: 2.4- to 7.1-fold).

Additionally, 4 of the 6 (67%) cabotegravir plus rilpivirine virologicfailures with post-baseline resistance data had on-treatment INSTIresistance-associated substitutions and reduced phenotypicsusceptibility to cabotegravir (Q148R [n=2; 5-fold and 9-fold decreasedsusceptibility to cabotegravir], G140R [n=1; 7-fold decreasedsusceptibility to cabotegravir], or N155H [n=1; 3-fold decreasedsusceptibility to cabotegravir]).

In comparison, 2 of the 7 (29%) virologic failures in the CAR arm whohad post-baseline resistance data had on-treatment resistancesubstitutions and phenotypic resistance to their antiretroviral drugs;both had on-treatment NRTI substitutions, M184V or I, which conferredresistance to emtricitabine or lamivudine in their regimen and 1 of themalso had the on-treatment NNRTI resistance substitution G190S,conferring resistance to efavirenz in their regimen.

In Phase 2 clinical trial LATTE-2, virologic failures on cabotegravirplus rilpivirine also showed emergent genotypic and phenotypiccabotegravir and rilpivirine resistance (with emergent INSTIresistance-associated substitution Q148R and NNRTI resistance-associatedsubstitutions K103N, E138G, and K238T).

In Phase 2 clinical trial LATTE, virologic failures on oral cabotegravirplus rilpivirine also showed emergent genotypic and phenotypiccabotegravir and NNRTI resistance (with emergent INSTIresistance-associated substitutions Q148R, E138K+Q148R,E138K+G140A+Q148R, and G140S+Q148R, and rilpivirineresistance-associated substitutions E138Q, K101K/E+E138E/A,K101K/E+E138E/K, K101E+M230L, and K101E.

Five of the 7 cabotegravir plus rilpivirine virologic failures in FLAIRand ATLAS had HIV-1 subtype A1 and had the integrase L74I substitution(IN L74I) detected at baseline and failure timepoints. Subjects withsubtype A1 infection whose virus did not have IN L74I at baseline didnot experience virologic failure (FLAIR results shown in Table 12). Inaddition, there was no detectable phenotypic resistance to cabotegravirconferred by the presence of IN L74I at baseline.

The other 2 virologic failures had subtype AG and did not have the INL74I substitution. Six of the virologic failures with subtype A1 and AGwere from Russia where the prevalence of subtypes A, A1, and AG arehigh. Subtypes A, A1, and AG are uncommon in the United States.

The presence of the IN L74I substitution in other subtypes, such assubtype B commonly seen in the United States, was not associated withvirologic failure (Table 12). In contrast to the Phase 3 trials whereall virologic failures were subtype A1 or AG, in Phase 2 clinicaltrials, subtypes of the cabotegravir plus rilpivirine virologic failuresincluded A1, A, B, and C.

TABLE 12 Rate of Virologic Failure in FLAIR Trial: Baseline Analysis(Subtypes A1 and B, and Presence of IN L74I) Cabotegravir plus CurrentAntiretroviral Virologic Failure Rate Rilpivirine^(a) Regimen^(b)Subtype A1 3/8 (38%) 1/4 (25%) +IN L74I 3/5 (60%) 1/3 (33%) −IN L74I 0/30/1 Subtype B 0/174 2/174 (1.2%) +IN L74I 0/12   0/11 −IN L74I 0/1532/150 (41.3%) Missing 0/9    0/13 Russian 4/54 (7.4%) 1/39 (2.6%) +INL74I 3/35 (9%) 1/29 (43.4%) −IN L74I 1/12 (8.3%) 0/7 Missing 0/7   0/3^(a)There were 4 virologic failures in the cabotegravir arm. Onevirologic failure in the cabotegravir arm had subtype AG. ^(b)There were3 virologic failures in the CAR arm. Two virologic failures in thecabotegravir arm had subtype B.Cabotegravir: Cross-resistance has been observed among INSTIs.Cabotegravir had reduced susceptibility (>5-fold change) to recombinantHIV-1 strain NL432 viruses harboring the following integrase amino acidsubstitutions: G118R, Q148K, Q148R, T66K+L74M, E92Q+N155H, E138A+Q148R,E138K+Q148K/R, G140C+Q148R, G140S+Q148H/K/R, and Q148R+N155H (range:5.1- to 81-fold). The substitutions E138K+Q148K and Q148R+N155Hconferred the greatest reductions in susceptibility of 81- and 61-fold,respectively.Cabotegravir was active against viruses harboring the NNRTIsubstitutions K103N or Y188L, or the NRTI substitutions M184V,D67N/K70R/T215Y, or V75I/F77L/F116Y/Q151M.Rilpivirine: Cross-resistance has been observed among NNRTIs. The singleNNRTI substitutions K101P, Y181I, and Y181V conferred 52-, 15-, and12-times fold change to rilpivirine, respectively. The K103Nsubstitution did not show reduced susceptibility to rilpivirine byitself. Combinations of 2 or 3 NNRTI resistance-associated substitutionsgave 3.7- to 554-fold change to rilpivirine in 38% and 66% ofsubstitutions, respectively. Considering all available cell culture andclinical data, any of the following amino acid substitutions, whenpresent at baseline, are likely to decrease the antiviral activity ofrilpivirine: K101E and P; E138A, G, K, R, and Q; V179L; Y181C, I, and V;Y188L; H221Y; F227C; M230I and L, and the combination of L100I/K103N.

According to another aspect of the main embodiment, carcinogenesis,mutagenesis, impairment of fertility were reviewed.

Cabotegravir was not carcinogenic in long-term studies in the mouse andrat. Rilpivirine was not carcinogenic in rats. In mice, rilpivirine waspositive for hepatocellular neoplasms in both males and females. Theobserved hepatocellular findings in mice may be rodent specific. At thelowest tested doses in mice, the systemic exposures (based on AUC) torilpivirine were >17 times the exposure in humans at the MRHD of 25 mgonce daily in HIV-1-infected patients or 600-mg IM injection dose ofrilpivirine extended-release injectable suspension.

Cabotegravir was not genotoxic in the bacterial reverse mutation assay,mouse lymphoma assay, or in the in vivo rodent micronucleus assay.

Rilpivirine was not genotoxic in the bacterial reverse mutation assay,mouse lymphoma assay, or in the in vivo rodent micronucleus assay.

No human data on the effect of cabotegravir on fertility are available.Cabotegravir when administered orally to male and female rats at 1,000mg/kg/day (exposure [AUC] >30 times MRHD of 30 mg/day dosed orally or400-mg intramuscular injection dose) for up to 26 weeks did not causeadverse effects on male or female reproductive organs orspermatogenesis. No functional effects on mating or fertility wereobserved in male or female rats when administered cabotegravir at dosesup to 1,000 mg/kg/day.

No human data on the effect of rilpivirine on fertility are available.In a study conducted in rats, there were no effects on mating orfertility with rilpivirine up to 400 mg/kg/day, a dose of rilpivirinethat showed maternal toxicity. This dose is associated with an exposurethat is >28 times the exposure in humans at the MRHD of 25 mg once dailyor 600-mg intramuscular injection dose of rilpivirine extended-releaseinjectable suspension.

The efficacy of the Combination has been evaluated in two Phase 3randomized, multicenter, active-controlled, parallel-arm, open-label,non-inferiority trials: Trial 201584 (FLAIR, [NCT02938520]), (n=629):HIV-1-infected, antiretroviral treatment (ART)-naive subjects received adolutegravir INSTI-containing regimen for 20 weeks (eitherdolutegravir/abacavir/lamivudine or dolutegravir plus 2 other NRTIs ifsubjects were HLA-B*5701 positive). Subjects who were virologicallysuppressed (HIV-1 RNA <50 copies/mL, n=566) were then randomized (1:1)to receive either a cabotegravir plus rilpivirine regimen or remain onthe current antiretroviral regimen. Subjects randomized to receivecabotegravir plus rilpivirine initiated treatment with daily orallead-in dosing with one 30-mg cabotegravir tablet plus one 25-mgrilpivirine tablet for at least 4 weeks followed by treatment withcabotegravir extended-release injectable suspension plus rilpivirineextended-release injectable suspension for an additional 44 weeks.

Trial 201585 (ATLAS, [NCT02951052]), (n=616): HIV-1-infected,ART-experienced, virologically-suppressed (for at least 6 months; medianprior treatment duration was 4.3 years) subjects (HIV-1 RNA <50copies/mL) were randomized and received either a cabotegravir plusrilpivirine regimen or remain on their current antiretroviral regimen.Subjects randomized to receive cabotegravir plus rilpivirine initiatedtreatment with daily oral lead-in dosing with one 30-mg cabotegravirtablet plus one 25-mg rilpivirine tablet for at least 4 weeks followedby treatment with cabotegravir extended-release injectable suspensionplus rilpivirine extended-release injectable suspension for anadditional 44 weeks.

The primary analysis was conducted after all subjects completed theirWeek 48 visit or discontinued the trial prematurely.

At baseline in the pooled analysis, in subjects randomized to receivethe Combination, the median age was 38 years, 27% were female, 27% werenon-white, and 7% had CD4+ cell count <350 cells/mm³; thesecharacteristics were similar between treatment arms. In ATLAS, subjectsreceived an NNRTI (50%), integrase inhibitor (33%), or proteaseinhibitor (17%) as their baseline third-agent class prior torandomization; this was similar between treatment arms.

The primary endpoint of FLAIR and ATLAS was the proportion of subjectswith plasma HIV-1 RNA ≥50 copies/mL at Week 48 (snapshot algorithm forthe Intent-to-Treat-Efficacy [ITT-E] population).

In a pooled analysis of FLAIR and ATLAS, the Combination wasnon-inferior to current antiretroviral regimen on the proportion ofsubjects having plasma HIV-1 RNA ≥50 copies/mL (1.9% and 1.7%,respectively) at Week 48. The adjusted treatment difference between theCombination and current antiretroviral regimen (0.2; 95% CI: −1.4, 1.7)for the pooled analysis met the non-inferiority criterion (upper boundof the 95% CI: below 4%). Furthermore, in the pooled analysis, theCombination was non-inferior to current antiretroviral regimen on theproportion of subjects having plasma HIV-1 RNA <50 copies/mL (93.1% and94.4%, respectively) at Week 48. The adjusted treatment differencebetween cabotegravir plus rilpivirine and current antiretroviral regimen(−1.4; 95% CI: −4.1, 1.4) for the pooled analysis met thenon-inferiority criteria (lower bound of the 95% CI: above −10%).

The non-inferiority result established in FLAIR and ATLAS demonstratedthat the length of HIV-1 RNA virologic suppression prior to initiationof the Combination (i.e., <6 months or ≥6 months) did not impact overallresponse rates.

The primary endpoint and other Week 48 outcomes, including outcomes bykey baseline factors, for FLAIR and ATLAS are shown in Tables 13 and 14.

TABLE 13 Virologic Outcomes of Randomized Treatment in FLAIR and ATLASTrials at Week 48 (Snapshot Algorithm) FLAIR ATLAS CAB CAB plus plus RPVCAR RPV CAR Virologic Outcomes (n = 283) (n = 283) (n = 308) (n = 308)HIV-1 RNA ≥ 50 copies/mL^(a) 2% 2% 2% 1% Treatment Difference −0.4% 0.7%(95% CI: −2.8%, 2.1%) (95% CI: −1.2%, 2.5%) HIV-1 RNA < 50 copies/mL94%  93%  93%  95%  No virologic data at Week 48 window 4% 4% 6% 4%Discontinued due to adverse event or death 3% <1%  4% 2% Discontinuedfor other reasons 1% 4% 2% 2% Missing data during window but on study 00 0 0 ^(a)Includes subjects who discontinued for lack of efficacy anddiscontinued while not suppressed. ^(b)Adjusted for randomizationstratification factors. n = Number of subjects in each treatment group,CI = Confidence interval, CAB = Cabotegravir, RPV = Rilpivirine, CAR =Current antiretroviral regimen.

TABLE 14 Proportion of Subjects in FLAIR and ATLAS Trials with PlasmaHIV-1 RNA ≥ 50 copies/mL at Week 48 for Key Baseline Factors (SnapshotAlgorithm). FLAIR ATLAS CAB CAB plus plus RPV CAR RPV CAR (N = 283) (N =283) (N = 308) (N = 308) Baseline Factors n/N (%) n/N (%) n/N (%) n/N(%) Baseline CD4+ (cells/mm3) <350 0/19 1/27 (3.7%) 0/23 1/27 (3.7%)≥350 to <500 3/64 (4.7%) 0/60 2/56 (3.6%) 0/60 ≥500 3/200 (1.5%) 6/196(3.1%) 3/299 (1.3%) 2/224 (0.9%) Gender Male 3/220 (1.4%) 6/219 (2.7%)3/209 (1.4%) 3/204 (1.5%) Female 3/63 (4.8%) 1/64 (1.6%) 2/99 (2.0%)0/104 Race White 6/216 (2.8%) 5/201 (2.5%) 3/214 (1.4%) 2/207 (1.0%)African American/African 0/47 2/56 (3.6%) 2/62 (3.2%) 1/77 (1.3%)Heritage Asian/Other 0/20 0/24 0/32 0/24 BMI <30 kg/m² 3/243 (1.2%)7/246 (2.8%) 3/248 (1.2%) 1/242 (0.4%) ≥30 kg/m² 3/40 (7.5%) 0/37 2/60(3.3%) 2/66 (3.0%) Age (years) <50 5/250 (2.0%) 6/254 (2.4%) 4/242(1.7%) 2/212 (0.9%) ≥50 1/33 (3.0%) 1/29 (3.4%) 1/66 (1.5%) 1/96 (1.0%)Baseline antiviral therapy at randomization Proteaseinhibitor-containing 0 0 1/51 (2.0%) 0/54 regimen Integraseinhibitor-containing 6/283 (2.1%) 7/283 (2.5%) 0/102 2/99 (2.0%) regimenNon-nucleoside reverse 0 0 4/155 (2.6%) 1/55 (0.6%) transcriptaseinhibitor-containing regimenIn both the FLAIR and ATLAS trials, treatment differences acrossbaseline characteristics (CD4+ count, gender, age, race, BMI, andbaseline third-agent class) were comparable. Subjects in both the FLAIRand ATLAS trials were virologically-suppressed prior to Day 1 or atstudy entry, respectively, and no clinically relevant change frombaseline in CD4+ cell counts was observed.

According to another aspect of the main embodiment, the Combination issupplied in 2 dosing kits containing cabotegravir extended-releaseinjectable suspension 200 mg/mL and rilpivirine extended-releaseinjectable suspension 300 mg/mL, co-packaged as follows:

2-mL (NDC 49702-253-15) containing:

-   -   One 2-mL single-dose vial of cabotegravir extended-release        injectable suspension containing 400 mg of cabotegravir.    -   One 2-mL single-dose vial of rilpivirine extended-release        injectable suspension containing 600 mg of rilpivirine        3-mL (NDC 49702-240-15) containing:    -   One 3-mL single-dose vial of cabotegravir extended-release        injectable suspension containing 600 mg of cabotegravir.    -   One 3-mL single-dose vial of rilpivirine extended-release        injectable suspension containing 900 mg of rilpivirine.        Each 2-mL and 3-mL dosing kit also contains 2 syringes, 2 vial        adapters, and 2 needles for intramuscular injection (23-gauge,        1½ inch). The vial stoppers are not made with natural rubber        latex.

In an embodiment, the 2-mL single-dose vial of cabotegravirextended-release injectable suspension containing 400 mg ofcabotegravir, the 2-mL single-dose vial of rilpivirine extended-releaseinjectable suspension containing 600 mg of rilpivirine, the 3-mLsingle-dose vial of cabotegravir extended-release injectable suspensioncontaining 600 mg of cabotegravir, and the 3-mL single-dose vial ofrilpivirine extended-release injectable suspension containing 900 mg ofrilpivirine are packed separately. In an embodiment, each of the 2-mLand 3-mL packages also contain a syringe, a vial adapter and a needlefor intramuscular injection (23-gauge, 1½ inch). The vial stoppers arenot made with natural rubber latex.

According to another aspect of the main embodiment, the Combination isstored in the refrigerator at 2° to 8° C. (36° to 46° F.) in theoriginal carton until ready to use. Preferably, neither the Combination,nor either component of the Combination is frozen. Preferably, neitherthe Combination nor any component of the Combination is mixed with anyother product or diluent.

Prior to administration, vials should be brought to room temperature(not to exceed 25° C. [77° F.]). Vials may remain in the carton at roomtemperature for up to 6 hours. If not used after 6 hours, they must bediscarded.

Once the suspension has been drawn into the respective syringes, theinjections should be administered as soon as possible, but may remain inthe syringe for up to 2 hours. If 2 hours are exceeded, the medications,syringes, and needles must be discarded.

As used throughout, one of skill in the art recognizes that the terms“monthly” or similar are interchangeable with “every 4 weeks” or “Q4W”.Similarly, terms referring to every 2 months are equivalent for purposesof administration with every 8 weeks or “Q8W”. For purposes herein, anymonth versus 4 week period (or multiple thereof) shall be taken asalternative embodiments.

Second Main Embodiment

According to a second main embodiment, there is provided a method oftreating HIV-1, comprising regularly administering intramuscularinjections of cabotegravir or a salt thereof and rilpivirine or a saltthereof, subsequent to at least one said intramuscular injection of eachof cabotegravir or a salt thereof and rilpivirine or a salt thereof,discontinuing one or both of said regularly administered intramuscularinjections, and replacing the one or more discontinued intramuscularinjection with regularly administered oral therapy.

The method of treating HIV comprises the use of cabotegravir and/orrilpivirine oral therapy administered subsequent to at least onecabotegravir and/or rilpivirine injection. According to an embodiment,cabotegravir oral therapy is administered subsequent to at least onecabotegravir injection. Alternatively, rilpivirine oral therapy isadministered subsequent to at least one rilpivirine injection.

According to the embodiment, if a patient plans to miss a scheduledinjection visit, oral therapy is used in place of one or more injectionsafter initiation of the injection schedule. Injection dosing may beresumed on schedule after oral dosing, in which case the oral doseperforms the function of a bridging dose between injections. In anembodiment, in case more than 2 months need to be covered for, i.e.missing more than 2 monthly injections, an alternative oral regimenshould be initiated one month or 2 months (±7 days) after the finalintramuscular injection. In an embodiment, in case more than 2 monthsneed to be covered for, i.e. missing more than one every 2 monthsinjection, an alternative oral regimen should be initiated 2 months (±7days) after the final intramuscular injection.

By way of example, if a patient plans to miss a scheduled injectionvisit by more than 7 days, oral therapy (e.g. one 30-mg tablet ofcabotegravir and one 25-mg tablet of rilpivirine once daily) may be usedto replace injections. Preferably, the oral therapy replaces 2 or fewerinjections. The first dose of oral therapy should be taken approximatelywhen the missed injection would have been administered, e.g. 1 monthafter the last injection dose in the case of monthly administrationschedules. Injection dosing should be resumed on the day oral dosingcompletes (see Table 2 above). The first dose of oral therapy should betaken approximately when the missed injection would have beenadministered, e.g. 2 months (±7 days) after the last injection dose inthe case of two monthly administration schedules. Injection dosingshould be resumed on the day oral dosing completes.

By way of example, if a patient, who is on monthly injection dosing ofRilpivirine long acting, misses injections or oral therapy or is on oralbridging therapy by <2 months, the patient should continue with themonthly 600 mg (2 mL) injection dosing schedule as soon as possible. Byway of example, if a patient, who is on monthly injection dosing ofRilpivirine long acting, misses injections or oral therapy or is on oralbridging therapy by ≥2 months, the patient should re-initiate thepatient on the 900 mg (3 mL) dose, and then continue to follow themonthly 600 mg (2 mL) injection dosing schedule. (Table 15)

By way of example, if a patient, who is on 2 monthly injection dosing ofRilpivirine long acting, misses a scheduled injection visit or oraltherapy or is on oral bridging therapy by ≤2 months, the patient shouldresume with 3 mL (900 mg) injections of rilpivirine long actingformulation as soon as possible and continue with the every 2 monthsinjection dosing schedule. In an embodiment, the patient missedinjection 2 (month 3). By way of example, if a patient, who is on 2monthly injection dosing of Rilpivirine long acting, misses a scheduledinjection visit or oral therapy or is on oral bridging therapy by >2months, the patient should re-initiate treatment with a 3 mL (900 mg)injection of rilpivirine long acting formulation, followed by a second 3mL (900 mg) initiation injection of rilpivirine long acting formulationone month later. Then follow the every 2 months injection dosingschedule. In an embodiment, the patient missed injection 2 (month 3).(Table 16)

By way of example, if a patient, who is on 2 monthly injection dosing ofRilpivirine long acting, misses a scheduled injection visit or oraltherapy or is on oral bridging therapy by ≤3 months, the patient shouldresume with 3 mL (900 mg) injections of rilpivirine long actingformulation as soon as possible and continue with the every 2 monthinjection dosing schedule. In an embodiment, the patient missedinjection 3 or later (month 5 onwards). By way of example, if a patient,who is on 2 monthly injection dosing of Rilpivirine long acting, missesa scheduled injection visit or oral therapy or is on oral bridgingtherapy by >3 months, the patient should re-initiate treatment on the 3mL (900 mg) injections of rilpivirine long acting formulation, followedby a second 3 mL (900 mg) initiation injection of rilpivirine longacting formulation one month later. Then follow the every 2 monthinjection dosing schedule. In an embodiment, the patient missedinjection 3 or later (month 5 onwards). (Table 16).

TABLE 15 Rilpivirine long-acting dosing recommendations after missedinjections or oral therapy or on oral bridging therapy for patients onmonthly injection dosing Time since last injection Recommendation ≤2months: Continue with the monthly 600 mg (2 mL) injection dosingschedule as soon as possible. >2 months: Re-initiate the patient on the900 mg (3 mL) dose, and then continue to follow the monthly 600 mg (2mL) injection dosing schedule.

TABLE 16 Rilpivirine long-acting dosing recommendations after missedinjections or oral therapy or on oral bridging therapy for patients onevery 2 months injection dosing Missed Injection Time since Visit lastinjection Recommendation (all injections are 3 mL) Injection 2 ≤2 monthsContinue with the 900 mg (3 mL) injection as soon as (month 3) possibleand continue with every 2 months injection dosing schedule. >2 monthsRe-initiate the patient on the 900 mg (3 mL) dose, followed by a second900 mg (3 mL) initiation injection one month later. Then follow theevery 2 months injection dosing schedule. Injection 3 or ≤3 monthsContinue with the 900 mg (3 mL) injection as soon as later (month 5possible and continue with every 2 months injection onwards) dosingschedule. >3 months Re-initiate the patient on the 900 mg (3 mL) dose,followed by a second 900 mg (3 mL) initiation injection one month later.Then follow the every 2 months injection dosing schedule.

Third Main Embodiment

According to a third main embodiment, a method of treating HIV isprovided, comprising regularly administering intramuscular injections ofcabotegravir or a salt thereof and rilpivirine or a salt thereof,subsequent to at least one said intramuscular injection of each ofcabotegravir or a salt thereof and rilpivirine or a salt thereof,discontinuing one or both of said regularly administered intramuscularinjections, and reestablishing intramuscular administration of the oneor both cabotegravir or a salt thereof and rilpivirine or a saltthereof, by first administering a loading dose of the discontinuedcabotegravir or a salt thereof and/or rilpivirine or a salt thereof, andthen continuing the regular administration of the intramuscularinjections.

According to this embodiment, a re-initiation injection of theCombination is given after at least one prior injection and after delayof a subsequently scheduled injection outside of an allowable treatmentwindow, wherein the re-initiation injection is a higher dose than thescheduled injection.

According to one embodiment, re-initiation uses the 3-mL dose ofcabotegravir, and then continue to follow a monthly 2-mL injectiondosing schedule for cabotegravir. According to one embodiment,re-initiation uses the 3-mL dose of rilpivirine, and then continue tofollow a monthly 2-mL injection dosing schedule for rilpivirine.According to one embodiment, re-initiation uses the 3-mL dose of theCombination, and then continue to follow a monthly 2-mL injection dosingschedule for the Combination.

Fourth Main Embodiment

According to a fourth main embodiment, a method of treating HIV isprovided, comprising regularly administering intramuscular injections ofcabotegravir or a salt thereof and rilpivirine or a salt thereof,subsequent to viral suppression by a bictegravir-containing regimen.Alternatively, according to an aspect of this embodiment, there isprovided cabotegravir or a salt thereof and rilpivirine or a saltthereof for use in therapy, in particular in the treatment of HIVinfection, comprising regularly administering intramuscular injectionsof cabotegravir or a salt thereof and rilpivirine or a salt thereof,subsequent to viral suppression by a bictegravir-containing regimen.

According to this embodiment, the bictegravir-containing regimen is abictegravir/emtricitabine/tenofovir alafenamide single tablet regimen.Further according to this embodiment, the bictegravir is administered 50mg/day.

According to this embodiment, the regularly administered intramuscularinjections are administered approximately every 4 weeks, oralternatively, administered every month. According to anotherembodiment, the regularly administered intramuscular injections areadministered approximately every 8 weeks, or alternatively, administeredevery two months.

According to this embodiment, the method of regularly administeringintramuscular injections of cabotegravir or a salt thereof andrilpivirine or a salt thereof is clinically non-inferior to a treatmentwith the bictegravir-containing regimen. According to a furtherembodiment, the method of regularly administering intramuscularinjections of cabotegravir or a salt thereof and rilpivirine or a saltthereof is clinically non-inferior over a period of at least 12 months.

Example 1

ATLAS (NCT02951052) and FLAIR (NCT02938520) are two randomized,open-label, international phase 3 studies that demonstratednon-inferiority of switching to monthly intramuscular (IM) injections ofCAB LA+RPV LA vs. current antiretroviral regimen (CAR). The injectableCAB+RPV LA regimen requires monthly injection visits within apre-specified time window, representing a paradigm-shift for patientsfrom daily oral dosing.

Injections were scheduled Q4 weeks with a ±7-day dosing window of theprojected dosing date. Adherence to LA therapy was calculated as thenumber of on-time injection visits occurring within the dosing window,divided by the number of expected dosing visits through Week 48. Oralbridging (the use of oral dosing to cover planned missed injections) waspermitted in both trial protocols to enable dosing flexibility forplanned absences from a clinical site (e.g. for vacation or travel),while allowing subjects to remain on LA dosing in the long term.Injection visits outside the pre-specified window and missed injectionvisits with/without use of oral dosing were quantified.

From amongst the ATLAS and FLAIR clinical trials, oral dosing (CAB 30mg+RPV 25 mg) between in injections was used in 15 subjects in the 48Week study period.

6 subjects used oral bridging but did not miss a planned injectionvisit.2 subjects were unable to continue on LA therapy.9 missed injections occurred across both studies, with 8 covered by oralbridging (7 subjects).1 subject had a missed injection visit without coverage by planned oralbridging at Week 32 (stopping criteria met due to acute hepatitis A);however, LA therapy was continued at Week 36 and viral suppression wasmaintained.

TABLE 17 Summary of 7 subjects having missed injections bridged by oraltablet. Injection visit Duration (s) covered by of oral Viral load atPatient ATLAS/ oral bridging bridging restart Viral load at 48 Weeks #FLAIR (Week) (days) (copies/mL) (copies/mL) 1 FLAIR 16 and 20 53 <50 <502 FLAIR 48 29 <50 <50 3 FLAIR 48 20 <50 <50 4 ATLAS 32 28 <50 <50 5ATLAS 32 28 <50 <50 6 ATLAS 24 21 <50 <50 7 ATLAS 16 29 <50 <50For subjects with planned missed injection visits, oral bridging wasfound to be an effective strategy for maintaining virologic suppression;no cases of confirmed virologic failure were observed during a period oforal bridging or following resumption of IM dosing.

Example 2

A two-compartment model with first-order oral and intramuscular (IM)absorption and first-order elimination adequately described the datafrom 23,926 concentration records in 1647 subjects following oral and LAadministration (Han K, Patel P, Baker M, et al. Populationpharmacokinetics of cabotegravir in adult healthy subjects and HIV-1infected patients following administration of oral tablet and longacting intramuscular injection. Abstract WEPDB0205. 22nd InternationalAIDS Conference 23-27 Jul. 2018, Amsterdam, the Netherlands).

Covariates retained in the model included gender, BMI, needle length,and split injection on absorption rate constant following LAadministration (KA LA) and current smoker status and body weight on CLand volume. No CAB dose adjustment is necessary for the covariatesevaluated.

The 5th percentile of the individual predicted concentration (IPRED) oftrough following the loading dose in Phase 3 studies from the finalmodel output (0.65 μg/mL) was used as a benchmark to assess the impactof aberrations in dosing against the standard regimen (Orkin C, ArastéhK, Hemández-Mora M G, et al. Long-acting cabotegravir+rilpivirine forHIV maintenance: FLAIR week 48 results. Conference on Retroviruses andOpportunistic Infections (CROI). Abstract Number: 140. Mar. 4-7, 2019,Seattle, Wash.; Swindells S, Andrade-Villanueva J F, Richmond G J, etal. Long-acting cabotegravir+rilpivirine as maintenance therapy: ATLASweek 48 results. Conference on Retroviruses and Opportunistic Infections(CROI). Abstract Number: 139. Mar. 4-7, 2019, Seattle, Wash.). Theprotein-adjusted IC90 (PA-IC90, 0.166 μg/mL) was also considered whenassessing the acceptability of a dosing delay.

Long-term safety threshold was assigned of 13.1 μg/mL, the mediansteady-state Cmax following the highest oral dose of CAB 60 mg QDadministered for 96 weeks in Study LAI116482 (LATTE) (Margolis D A,Brinson C C, Smith G H R, et al. LAI116482 Study Team. Cabotegravir plusrilpivirine, once a day, after induction with cabotegravir plusnucleoside reverse transcriptase inhibitors in antiretroviral-naiveadults with HIV-1 infection (LATTE): a randomised, phase 2b,dose-ranging trial. Lancet Infect Dis. 2015 October; 15(10):1145-1155).

1- to 12-week delays in dosing of the 2nd, 3rd, and 4th injection weresimulated (Table 1). Q4W dosing was resumed after each delay.

A blended population of males (80%) and females (20%) was assumed torepresent the expected population. Each scenario included 5000 virtualsubjects to ensure 1000 female virtual subjects. Individual PKparameters were calculated by the population parameter estimates,subject-specific NONMEM inter-individual errors (ETAs) sampled from thedistributions that are decided by the estimated variance-covariatematrix of between-subject variability and by subject-specificcovariates.

Scenarios of Delayed Dosing for CAB Monthly Treatment Regimen (CAB LA600 mg (3 mL) Initial Injection Followed by 400 mg (2 mL) with RPV LAQ4W) (Table 18)

Oral bridging started at the time of the missed injection for a durationof 1-2 months when CAB LA dosing was resumed (Table 18). The 4th IM dosewas assumed to be missed. Dosing resumed the Q4W pattern.

TABLE 19 Sim Time Relative to 1^(st) LA Dose (Time Zero) in Weeks # OB 04 8 12 13 14 15 16 17 18 19 20 32 4 3 2 2 OB OB OB OB 2 2 33 6 3 2 2 OBOB OB OB OB OB 2 34 8 3 2 2 OB OB OB OB OB OB OB OB 2 35 8 3 2 2 OB OBOB OB OB OB OB OB 3OB: duration of oral bridging in weeks. Sim: simulation. 3=600 mg (3mL). 2=400 mg (2 mL). OB=oral bridging daily.

The results of the simulations run in accordance with the above areshown in FIG. 1. Simulated Concentration-versus-Time Profiles for a) nodelay (Sim #1), b) Injection 2 delayed by 1 week (Sim #2), c) Injection3 delayed by 4 weeks with 2 mL or 3 mL re-initiation (Sim #15, Sim #16),d) Injection 4 delayed by 4 weeks with 2 mL or 3 mL re-initiation (Sim#25, Sim #26), e) 4-week delay at Injection 4 with and without oralbridge (Sim #25, Sim #32) and f) 8-week delay at Injection 4 with andwithout oral bridge (Sim #29, Sim #35).

1. A method of treating HIV-1, comprising regularly administeringintramuscular injections of cabotegravir or a salt thereof andrilpivirine or a salt thereof, subsequent to at least one saidintramuscular injection of each of cabotegravir or a salt thereof andrilpivirine or a salt thereof, discontinuing one or both of saidregularly administered intramuscular injections, and replacing the oneor more discontinued intramuscular injection with regularly administeredoral therapy.
 2. The method of claim 1, wherein the intramuscularinjections of cabotegravir or a salt thereof and rilpivirine or a saltthereof are administered separately.
 3. The method of claim 2, whereinthe cabotegravir or salt thereof is administered as a 400 mgintramuscular injection once per month, and wherein the rilpivirine orsalt thereof is administered as a 600 mg intramuscular injection onceper month.
 4. The method of claim 3, wherein the cabotegravir or saltthereof is administered as a 600 mg intramuscular injection once andthen a 400 mg intramuscular injection once per month thereafter, andwherein the rilpivirine or salt thereof is administered as a 900 mgintramuscular injection once and then as a 600 mg intramuscularinjection once per month thereafter.
 5. The method of claim 2, whereinthe cabotegravir or salt thereof is administered as a 600 mgintramuscular injection once per 2 months, and wherein the rilpivirineor salt thereof is administered as a 900 mg intramuscular injection onceper 2 months.
 6. (canceled)
 7. The method of claim 1, wherein saidregular administration is once every month+/−7 days or once every 2months+/−7 days.
 8. (canceled)
 9. The method of claim 1, wherein orallead-in doses of both cabotegravir or a salt thereof and rilpivirine ora salt thereof are provided prior to regularly administeringintramuscular injections.
 10. The method of claim 1, whereinintramuscular administration of cabotegravir or a salt thereof isdiscontinued and replaced with one 30-mg tablet of cabotegravir or saltthereof once daily.
 11. The method of claim 1, wherein intramuscularadministration of rilpivirine or a salt thereof is discontinued andreplaced with one 25-mg tablet of rilpivirine or salt thereof oncedaily.
 12. The method of claim 10, wherein regular intramuscularadministration of said cabotegravir or a salt thereof is reinitiatedafter said oral therapy of said cabotegravir or a salt thereof.
 13. Amethod of treating HIV-1, comprising regularly administeringintramuscular injections of cabotegravir or a salt thereof andrilpivirine or a salt thereof, subsequent to at least one saidintramuscular injection of each of cabotegravir or a salt thereof andrilpivirine or a salt thereof, discontinuing one or both of saidregularly administered intramuscular injections, and reestablishingintramuscular administration of the one or both cabotegravir or a saltthereof and rilpivirine or a salt thereof, by first administering aloading dose of the discontinued cabotegravir or a salt thereof and/orrilpivirine or a salt thereof, and then continuing the regularadministration of the intramuscular injections.
 14. The method of claim13, where the intramuscular injections of cabotegravir or a salt thereofand rilpivirine or a salt thereof are administered separately.
 15. Themethod of claim 13, wherein the regularly administered injectionscomprise the cabotegravir or salt thereof administered as a 400 mgintramuscular injection once per month, and wherein the rilpivirine orsalt thereof administered as a 600 mg intramuscular injection once permonth.
 16. The method of claim 13, wherein the loading dose comprisescabotegravir or salt thereof administered as a 600 mg intramuscularinjection once and/or rilpivirine or salt thereof administered as a 900mg intramuscular injection once.
 17. The method of claim 13, wherein theregularly administered injections comprise the cabotegravir or saltthereof administered as a 600 mg intramuscular injection once per 2months, and wherein the rilpivirine or salt thereof administered as a900 mg intramuscular injection once per 2 months.
 18. (canceled)
 19. Themethod of claim 13, wherein said regular administration is once everymonth+/−7 days or once every 2 months+/−7 days.
 20. (canceled)
 21. Themethod of claim 13, wherein an oral lead-in doses of both cabotegraviror a salt thereof and rilpivirine or a salt thereof are provided priorto regularly administering intramuscular injections.
 22. (canceled) 23.(canceled)
 24. (canceled)
 25. (canceled)
 26. (canceled)
 27. (canceled)28. (canceled)
 29. (canceled)
 30. (canceled)
 31. (canceled) 32.(canceled)
 33. (canceled)
 34. (canceled)
 35. (canceled)
 36. (canceled)37. (canceled)
 38. (canceled)
 39. (canceled)
 40. (canceled) 41.(canceled)
 42. (canceled)
 43. The method of claim 11, wherein regularintramuscular administration of said rilpivirine or a salt thereof isreinitiated after said oral therapy of said rilpivirine or a saltthereof.
 44. The method of claim 10, wherein intramuscularadministration of rilpivirine or a salt thereof is discontinued andreplaced with one 25-mg tablet of rilpivirine or salt thereof oncedaily.
 45. The method of claim 44, wherein regular intramuscularadministration of said cabotegravir or a salt thereof and/or rilpivirineor a salt thereof is reinitiated after said oral therapy of saidcabotegravir or a salt thereof and/or rilpivirine or a salt thereof. 46.The method of claim 15, wherein the loading dose comprises cabotegraviror salt thereof administered as a 600 mg intramuscular injection onceand/or rilpivirine or salt thereof administered as a 900 mgintramuscular injection once.
 47. The method of claim 17, wherein theloading dose comprises cabotegravir or salt thereof administered as a600 mg intramuscular injection once and/or rilpivirine or salt thereofadministered as a 900 mg intramuscular injection once.